MXPA06009470A - Modulation of inflammatory and metastatic processes - Google Patents

Abstract

Methods of using compounds having Structure (I) or the salts or tautomers of the compounds in the treatment of disorders relating to cell adhesion and metastatic processes are presented herein.

Description

MODULATION OF INFLAMMATORY AND METASTASIC PROCESSES Field of the Invention The present invention provides methods for using compounds to modulate inflammatory responses and processes related to tumor metastasis. The invention further provides methods for monitoring the effects of the compounds of the invention by measuring the levels of ICAM, VCAM, or E-selectin molecules in a subject treated with the compounds. Background of the Invention Amino quinolinone benzimidazolyl compounds such as 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) - Ona and its tautomers and salts are potent inhibitors of various classes of kinases such as VEGFR2 (KDR, Flk-1), FGFR1 and PDGFRβ with IC50s in the range of 10-27 nM. See U.S. Patent No. 6,605,617, U.S. Patent Application No. 10 / 644,055, and U.S. Patent Application No. 10 / 706,328, each of which it is incorporated herein by reference in its entirety and for all purposes as if fully indicated herein, for a list of various tyrosine and serine / threonine kinases for which 4-amino-5-fluoro-3- [ 6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (1H) -one has shown REF .: 175200 activity and for assay procedures. Such kinases are important for the initiation and maintenance of growth of new blood vessels as well as for tumor proliferation. As a result these inhibitors have applications in the treatment of various disorders such as solid and hematological cancers. The identification of plasma biomarkers in subjects treated with these kinase inhibitors can therefore provide a convenient method for monitoring the physiological response of the subject to treatment. Cell adhesion molecules play important roles in tumor cell invasion, metastasis, and interaction with immune cells. VCAM (vascular cell adhesion molecule) is a transmembrane glycoprotein and expressed in endothelial cells and various types of cancers such as bladder, breast, gastrointestinal, ovarian, renal and Hodgkin's lymphoma and not Hodgkin's . VCAM is induced by VEGF and is expressed predominantly in activated endothelial cells. ICAM (inducible cell adhesion molecule) is also expressed in endothelial cells and several cells that include fibroblasts, hematopoietic cells and tumor cells. The soluble form of the ICA; present in the plasma is generated by proteolytic cleavage of molecules associated with the membrane. E-selectin (endothelial leukocyte adhesion molecule) is a transmembrane glycoprotein expressed on endothelial cells and measured the adhesion of neutrophils, monocytes and T cells to endothelial cells. E-selectin also mediates tumor progression and metastasis. A high concentration of soluble ICAM, VCAM and E-selectin is considered a marker of endothelial cell activation during tumor development, metastasis and inflammatory responses. These cell adhesion molecules located in the endothelial cells can mediate the adhesion of metastatic tumor cells and allow extravasation in the vessels. It is of interest that these molecules are inducible, being poorly expressed in normal endothelial cells but capable of being highly expressed after exposure to cytosines such as IL-1 or TNF-α. In addition, some of these molecules are expressed preferentially in different vascular beds, with the VCAM that is abundant in the lung and E-selectin in the liver. Matrix metalloproteases (MMPs) are a class of proteases that degrade most components of the extracellular matrix (ECM for its acronym in English). Under normal physiological conditions you are playing an important role in the development, tissue remodeling and morphogenesis. However, elevated levels of certain metalloproteases have been implicated in pathological diseases such as cancer and inflammation. Degradation of the extracellular matrix in the basement membrane is essential for tissue invasion by tumor cells and metastasis at several sites, and this degradation is dependent on the activity of the MMP. The MMP family includes more than 20 members. Two of these proteases are MMP-2 (gelatinase A, 72 KD) and MMP-9 (gelatinase B, 92 KD). MMP-2 and MMP-9 are important regulators of cancer progression and metastasis and their levels are frequently elevated in several cancer patients. A report by Bergers et al. (matrix metalloproteinase-9 activates the angiogenic key during carcinogenesis; Berger, G. et al., Nature Cell Biology, 2: 737-744; 2000) describes that MMP-9 / gelatinase B is a functional component of an angiogenic key during multistage pancreatic carcinogenesis by increasing the release of VEGF. Various benzimidazole quinolinone compounds useful for inhibiting vascular endothelial growth factor receptor angiogenesis and tyrosine kinases and for inhibiting other tyrosine and serine / threonine kinases including 4-amino-5-fluoro-3- [5- (4-methylpiperazine- 1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) -one or a tautomer thereof and the synthesis thereof are described in the following documents which are each incorporated herein by reference in its totalities and for all purposes as if totally indicated herein: United States Patent No. 6,605,617, United States Patent No. 6,756,383; US Patent Application No. 10 / 116,117 filed (published February 6, 2003, as the Application of the United States of America 2003/0028018 Al); Application of the United States of America No. 10 / 644,055 (published May 13, 2004, United States of America Patent Application No.2004 / 0092535); Application of the United States of America No. 10 / 903,174; Application of the United States of America No. 10 / 706,328, (published on November 4, 2004, as 2004/0220196); Application of the United States of America No. 10 / 982,757; and Application of United States of America No. 10 / 982,543. There is an important need for methods to modulate the levels of cell adhesion molecules and matrix metalloproteases. Such methods can therefore contribute to important and necessary therapies in the treatment of inflammatory and metastatic diseases mediated by cell adhesion molecules and matrix metalloproteases. Summary of the Invention The present invention relates to methods for treating a human or animal subject with, and uses in, a human or animal subject of, a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The invention also relates to the use of the compound, tautomer, salt of the compound, salt of the tautomer, or mixture thereof in the preparation of a medicament for use in the methods described herein. In one aspect, the invention provides a method for modulating an inflammatory response or reducing cell adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and / or cell adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof. In one aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or mixture thereof are used to modulate an inflammatory response. In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to reduce cell adhesion. In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or mixture thereof are used to lower the levels of ICAM, VCAM or E-selectin. In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof • used to reduce the levels of circulation of cell adhesion molecules. In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or mixture thereof are used to decrease the circulating levels of ICAM, VCAM, or E-selectin. In another aspect, the invention provides a method for monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture of them to the subject. In some embodiments, the cell adhesion molecule is selected from the inducible cell adhesion molecule (ICAM), the vascular cell adhesion molecule (VCAM), or the endothelial leukocyte adhesion molecule (E-selectin). Some such methods also include extracting a blood sample from the subject and then measuring the amount of at least one cell adhesion molecule in at least a portion of the sample. Other embodiments include administering the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject. - In another aspect, the invention provides a method for identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during or after the administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the compound. tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from the inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some embodiments, the method further includes administering the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, "the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject after measuring the amount of the cell adhesion molecule in the subject Structure I has the following formula: I Wherein, R1, R2, R3 and R4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -N02, -OH, -OR15 groups -NR16R17, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, (alkyl) (aryl) groups substituted and unsubstituted aminoalkyl, substituted and unsubstituted heterocyclylalkyl groups and -C (= 0) R1A R5, R6, R7 and R8 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, groups -N02, -OH, -OR19, groups -NR20R21, groups -SH, -SR22, -S (= 0) R23 groups, -S (= 0) 2R24 groups, substituted and unsubstituted CN, amidinyl groups, substituted and unsubstituted guanidinyl groups, primary alkyl groups, substituted and unsubstituted, secondary and tertiary, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups , substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, groups (alkyl) (aryl) substituted and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) R25 groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, groups substituted and unsubstituted alkoxyalkyl, aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups; R 12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH groups, alkoxy, aryloxy groups, -NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, groups substituted and unsubstituted alkylamino, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, groups -C (= 0) H, - C (= 0) -alkyl, groups -C (= 0) -aryl, groups -C (= 0) O-alkyl, groups -C (= 0) O-aryl, C (= 0) NH2, groups -C (= 0) H (alkyl), groups -C (= 0) H (aryl, groups -C (= 0) N (alkyl ) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) (alkyl) (aryl), groups -C (= 0) -heterocyclyl, groups -C (= 0) NH (heterocyclyl) ), groups -C (= 0) -N (heterocyclyl) 2, groups -C (= 0) -N (alkyl) (heterocyclyl), -C groups. { = 0) -N (aryl) (heterocyclyl), substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups. R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C ( = 0) H, ~ C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups C (= 0) NH (alkyl), groups -C (= 0) H (aryl), groups -C (= 0) (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, (alkyl) groups ) (aryl) substituted and unsubstituted aminoalkyl, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R16 and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -C (= 0) H, -C (= 0) -alkyl, C (= 0) -aryl groups, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) H (aryl), groups -C (= 0) (alkyl) 2, groups -C (= 0 ) (aryl) 2, groups-C (= 0) (alkyl) (aryl), groups -C (= 0) O-alkyl, C-groups (= 0) O-aryl, substituted and unsubstituted heterocyclylalkyl groups, groups substituted and unsubstituted aminoalkyl, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (ary-1) aminoalkyl groups, -C (= 0) -heterocyclyl groups, -C (= 0) -0-heterocyclyl groups, -C (= 0) NH (heterocycle) groups, -C (= 0) - (heterocyclyl) groups 2, -C groups (= 0) - N (alkyl) (heterocyclyl ), -C (= 0) - N (aryl) (heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted heterocyclyloxyalkyl groups and not replaced; R18, R23, R24, and R25 may be the same or different or are independently selected from the group consisting of H, -NH2, -NH (alkyl) groups, -NH (aryl) groups, -N (alkyl) 2 groups, -N (aryl) 2 groups, - (alkyl) (aryl) groups, NH (heterocyclyl) groups, - (heterocyclyl) groups (alkyl), -N (heterocyclyl) groups (aryl), - (heterocyclyl) groups, 2 groups substituted and unsubstituted alkyl, substituted and unsubstituted aryl groups, -OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, -NHOH groups, -N (alkyl) OH groups, groups -N (aryl) OH, -N (alkyl) -O-alkyl groups, - (aryl) O-alkyl groups, N- (alkyl) O-aryl groups, and -N (aryl) O-aryl groups; and R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. Additional objects, features and advantages of the invention will be apparent from the following detailed description. DETAILED DESCRIPTION OF THE FIGURES Figure 1 is a graph which shows the effects of the various amounts of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazole-2- il] quinolin-2 (IH) -one (Compound 1) in murine breast tumor model 4T1 (vehicle (circle indicated in gray); 10 mpk (frame), 30 pk (gray triangle); 60 mpk (X); 100 mpk (diamond); and 150 mpk (filled circle)). Subcutaneous tumor growth is inhibited (40-80% compared to control), liver metastasis is completely inhibited, and lung metastases are inhibited by 60-97% after 18 days of dosing. Figures 2A and 2B are graphs showing the dose-dependent reduction of soluble ICAM (Figure 2A, more than 70% inhibition with 100 or 150 mg / kg) and soluble VCAM (Figure 2B, 44-47% inhibition with 100 or 150 mg / kg) in the serum of mice with 4TÍ breast tumors when dosed with various amounts of 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazole- 2-yl] quinolin-2 (1H) -one. Figure 3 is a graph which shows the dose-dependent inhibition of mouse-specific soluble E-selectin in the serum of mice bearing the tumor 4T1 treated with 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (1H) -one. Figures 4A, 4B and 4C are graphs of the VEGF zymography and ELISA data (Figure 4B) showing the decrease in MMP9 and VEGF in mice with implanted KMl2L4a tumor cells when dosed for 7 days with 100 mg / kg of 4 amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) -one. Figure 5 is an image obtained by scanning showing the decrease in the expression of ICAM and VCAM when HUVEC in culture are treated with 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) - lH-benzimidazol-2-yl] quinolin-2 (1H). Figure 6 is a scan image showing the decrease in the expression of integrin a.5, not the integrin av when treating HUVEC in culture with 4-amino-5-fluoro-3- [6- (4- methylpiperazin-1-yl) -IH-benzimidazol-2-yl] quinolin-2 (1H). DETAILED DESCRIPTION OF THE INVENTION The following abbreviations and definitions are used throughout this application. The phrase "cell adhesion" as used herein, refers to cell adhesion. The amount of cell adhesion in a subject "can typically be correlated with the amounts of cell adhesion molecules, such as, but not limited to VCAM, ICAM and E-selectin in a subject." VCAM "is the abbreviation that is for vascular cell adhesion molecule. "ICAM" is the abbreviation that is for inducible cell adhesion molecule. "- selectin" is also known as endothelial leukocyte adhesion molecule. "4T1" is a murine cell line. "BALB / C" is a strain of mice used in tumor xenograft experiments. "bFGF" is the abbreviation that is for the basic fibroblast growth factor. "FGFR1" also referred to as bFGFR, is the abbreviation for a tyrosine kinase that interacts with fibroblast growth factor FGF. "FGF" is an abbreviation for the fibroblast growth factor that interacts with FGFR1. "FGFR3" is the abbreviation for receptor 3 of the tyrosine kinase fibroblast growth factor that is frequently expressed in cancers of the multiple myeloma type. "Flk-1" is the abbreviation for tyrosine kinase 1 of the fetal liver, also known as tyrosine kinase of the kinase insert domain or -KDR (human), also known as vascular endothelial growth factor receptor 2 or VEGFR2 (KDR (human), Flk-1 (mouse)). "PDGF" is the abbreviation that is for the platelet derived growth factor, PDGF interacts with PDGFRa and PDGFRβ for tyrosine kinases. "RTK" is the abbreviation that is for receptor tyrosine kinase. "VEGF" is the abbreviation that is for the vascular endothelial growth factor. "VEGF-RTK" is the abbreviation for tyrosine kinase of the vascular endothelial growth factor receptor. "ELISA" is the abbreviation for the enzyme-linked immunosorbent assay. "MMP-2" is the abbreviation which is for the matrix metalloprotease-2 [includes the 72 KD protein (pro MMP-2) and the 62 KD protein (active MMP-2)]. MMP-2 is also referred to as gelatinase A. "MMP-9" is the abbreviation that is for the matrix metalloprotease-9 [includes the 105 KD protein (pro MMP-2) and the 92 KD protein (MMP-9) active)]. MMP-9 is also referred to as gelatinase B. "Ki67" is a marker for cellular proliferation. "Caspase-3" is a marker of apoptosis. Activation of caspase-3 requires proteolytic processing of inactive caspase-3 in "cleaved caspase-3", which has 17 KD and 19 KD in size. "PARP" is the abbreviation that is for poly ADP-ribose polymerase and is a marker of apoptosis. It is a 116 KD protein and is cleaved in an 89 KD protein. "CD31" is a marker for endothelial cells. Immunostaining with anti-CD31 antibody in tumor section by immunohistochemistry will indicate the number of microvessels (or microvessel density) in tumors. Generally, the reference to a certain element such as hydrogen or H is understood to include all isotopes of that element. For example, if a group R is defined to include hydrogen or H, it also includes deuterium and tritium. The phrase "unsubstituted alkyl" refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by the example form: -CH (CH3) 2, -CH (CH3) (CH2CH3), - CH (CH2CH3) 2, -C (CH3) 3, -C (CH2CH3) 3, -CH2CH (CH3) 2, -CH2CH (CH3) CH2CH3), -CH2CH (CH2CH3) 2, -CH2C (CH3) 3, - CH2C (CH2CH3) 3, -CH (CH3) CH (CH3) (CH2CH3), CH2CH2CH (CH3) 2, -CH2CH2CH (CH3) (CH2CH3), -CH2CH2CH (CH2CH3) 2, CH2CH2C (CH3) 3, -CH2CH2C (CH2CH3) 3, -CH (CH3) CH2CH (CH3) 2, CH (CH3) CH (CH3) CH (CH3) 2, -CH (CH2CH3) CH (CH3) CH (CH3) (CH2CH3), and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl, norbornyl, bicyclo [2.2.2] octyl and such substituted rings with straight or branched chain alkyl groups as defined above. Thus, the phrase "unsubstituted alkyl groups" includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. The unsubstituted alkyl groups can be linked to one or more carbon atoms, oxygen atom, nitrogen atom / or sulfur atom, in the parent compound. Preferred unsubstituted alkyl groups include straight or branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. Such more unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred groups have from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight or branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and -CH (CH 3) 2. The phrase "substituted alkyl" refers to an unsubstituted alkyl group as defined above in which one or more bonds to a carbon or hydrogen are replaced by a bond to hydrogen and non-carbon atoms such as, but not limited to a, a halogen atom in halides such as F, Cl, Br and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and arylsulfide groups, sulfone groups, sulfonyl groups and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in several other groups. Substituted alkyl groups also include those groups in which one or more bonds to a carbon or hydrogen atom are replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is / are replaced by one or more bonds to fluorine atoms. An example of a substituted alkyl group is the trifluoromethyl group and the other alkyl groups containing the trifluoromethyl group. Other alkyl groups include those in which one or more bonds to a carbon or hydrogen atom are replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, aryloxy group, or heterocyclyloxy group. Still other alkyl groups include alkyl groups having an amine, alkylaryl, dialkylamino, arylamine, (alkyl) (aryl) amine, diarylamine, heterocyclylamine, (alkyl) (heterocyclyl) amine, (aryl) (heterocyclic) amine or diheterocyclylamine group . The phrase "unsubstituted aryl" refers to aryl groups that do not contain heteroatoms. This includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphtenyl by the exemplary form. Although the phrase "unsubstituted aryl" includes groups containing fused rings such as naphthalene, it does not include aryl groups having other groups such as alkyl or halo groups linked to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described above. A preferred unsubstituted aryl group is phenyl. However, unsubstituted aryl groups can be linked to one or more carbon atoms, oxygen atoms, nitrogen atom, and / or sulfur atom in the parent compound. The phrase "substituted aryl group" has the same meaning with respect to unsubstituted aryl groups that the substituted alkyl groups have with respect to unsubstituted alkyl groups. However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also include aryl groups in which one or more aromatic carbons of the group Aryl are linked to a substituted and / or unsubstituted alkyl, alkenyl or alkynyl group as defined herein. This includes linking arrangements in which two carbon atoms of an aryl group are linked to two atoms of an alkyl, alkenyl or alkynyl group to define a fused ring system (for example, dihydronaphthyl or tetrahydronaphthyl). In this way, the phrase "substituted aryl" includes, but is not limited to, tolyl, and hydroxyphenyl, among others. The phrase "unsubstituted alkenyl" refers to a straight and branched chain and cyclic groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, -CH = C (H) (CH3), -CH = C (CH3) 2, -C (CH3) = C (H) 2, -C (CH3) = C (H) (CH3), -C (CH2CH3) = CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The phrase "substituted alkenyl" has the same meaning with respect to unsubstituted alkenyl groups that the substituted alkyl groups have with respect to unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon with double bond to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon atom. carbon not involved in a double bond to another carbon. The phrase "unsubstituted alkynyl" refers to straight or branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to -C = CH), -CSC (CH3), C = C (CH2CH3), -C (H2) CeC (H), -C (H) 2C = C (CH3) and -C (H) 2C = C (CH2CH3) among others. The phrase "substituted alkynyl" has the same meaning with respect to unsubstituted alkynyl groups that substituted alkyl groups have with respect to unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is linked to a triple bond carbon bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon. The phrase "unsubstituted aralkyl" refers to unsubstituted alkyl groups as defined above in which a hydrogen or a carbon bonded to the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl (~ CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the methyl carbon is bonded to a benzene carbon, then the compound is an unsubstituted aralkyl group (ie, a benzyl group) . In this way the phrase includes, but is not limited to, groups such as benzyl, diphenyl ethyl and 1-phenylethyl (-CH (C6H5) (CH3)) among others. The phrase "substituted aralkyl" has the same meaning with respect to unsubstituted aralkyl groups as substituted aryl groups with respect to unsubstituted aryl groups. However, a substituted aralkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon and not hydrogen atom. Examples of substituted aralkyl groups include, but are not limited to, -CH2C (= 0) (CeH5) and -CH2 (2-methylphenyl) among others. The phrase "unsubstituted heterocyclyl" refers to both aromatic and non-aromatic ring compounds including monocyclic, bicyclic and polycyclic ring compounds such as, but not limited to, quinuclidyl, which contains 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O and S. Although the phrase "unsubstituted heterocyclyl" includes fused heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups having other groups such as alkyl or halo groups attached to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups.

Examples of heterocyclyl groups include, but are not limited to: rings of 3 to 8 unsaturated members containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), 3"to 8 saturated members containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, fused unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl: unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl: unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 carbon atoms nitrogen, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (for example, 2H-1,4-benzoxazinyl, etc.); rings of 3 to 8 unsaturated members containing 1 to 3 sulfur atoms and 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (for example, 1, 2, 3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolidinyl: saturated or unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodicyl, tetrahydrothiophene, tetrahydro.thiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (for example 2H-1, 4-benzothiazinyl, etc.), dihydrobenzothiazinyl (eg example, 2H-3,4-dihydrobenzothiazinyl, etc.), rings of 3 to 8 unsaturated members containing oxygen atoms such as, but not limited to, furyl; unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (eg, 1,3-benzodioxoyl, etc.); rings of 3 to 8 unsaturated members containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; 3 to 8 saturated member rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxatiano; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl, and unsaturated fused heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. The heterocyclyl group also includes those described in which one or more S atoms in the ring is double bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 membered rings. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in which the S atom of thiomorpholine it is linked to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan and tetrahydrofuran. The phrase "substituted heterocyclyl" refers to an unsubstituted heterocyclyl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, N-alkyl piperazinyl groups such as 1-methyl piperazinyl, piperazine-N-oxide, N-alkylpiperazine N-oxides, 2- phenoxy-thiophene, and 2-chloropyridinyl among others. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which the bond to the non-hydrogen atom is a bond to a carbon atom that is part of a substituted or unsubstituted aryl, substituted and unsubstituted aralkyl, or unsubstituted heterocyclyl group . Examples include but are not limited to 1-benzylpiperidinyl, 3-phenylthiomorpholinyl, 3- (pyrrolidin-1-yl) -pyrrolidinyl, and 4- (piperidin-1-yl) -piperidinyl. Groups such as N-alkyl-substituted piperazine groups such as N-methylpiperazine, substituted morpholine groups, and piperazine N-oxide groups such as piperazine N-oxide and N-alkylpiperazine N-oxides are examples of some groups substituted heterocyclyls. Groups such as substituted piperazine groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine and the like, substituted morpholine groups, piperazine N-oxide groups, and N-alkyl piperazine N-oxide groups are examples of some substituted heterocyclyl groups which are especially suitable as the R6 or R7 groups. The phrase "unsubstituted heterocyclylalkyl" refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl (~ CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl is bonded to carbon 2 of pyridine (one of the carbon bonded to the N of pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl group. The phrase "substituted heterocyclylalkyl" has the same meaning with respect to unsubstituted heterocyclylalkyl groups that the substituted aralkyl groups have with respect to unsubstituted aralkyl groups. However, a substituted heterocyclylalkyl group also includes the groups in which a non-hydrogen atom is linked to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group. In addition, a substituted heterocyclylalkyl group also includes groups in which a carbon bond or a hydrogen bond of the alkyl part of the group is replaced by a bond to a substituted or unsubstituted aryl group or substituted or unsubstituted aralkyl. Examples include but are not limited to phenyl- (piperidin-1-yl) -methyl and phenyl- (morpholin-4-yl) -methyl. The phrase "unsubstituted alkylaminoalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an alkyl group not substituted as defined above. For example, methyl (-CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an ethyl group, then the resulting compound is ~ CH2-N (H-) (CH2CH3) which is an unsubstituted alkylaminoalkyl group. The phrase "substituted alkylaminoalkyl" refers to an unsubstituted alkylaminoalkyl group as defined above except where one or more bonds to the carbon or hydrogen atom in one or both of the alkyl groups is replaced by a bond to a non-carbon atom or not hydrogen as described above with respect to substituted alkyl groups other than linking to the nitrogen atom in all alkylaminoalkyl groups which do not by themselves qualify all alkylaminoalkyl groups as they are being substituted. However, substituted alkylaminoalkyl groups include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and not hydrogen atom.

The phrase "unsubstituted dialkylaminoalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom which binds to two other non-substituted alkyl groups substituted different or similar as defined above. The phrase "substituted dialkylaminoalkyl" refers to an unsubstituted dialkylaminoalkyl group as defined above in which one or more bonds to a carbon or hydrogen atom in one or more of the alkyl groups is replaced by a bond to a non-substituted carbon and not hydrogen as described with respect to substituted alkyl groups. The linkage to the nitrogen atom in all the dialkylaminoalkyl groups does not by itself qualify all the dialkylaminoalkyl groups as it is being substituted. The phrase "unsubstituted alkoxy" refers to a hydroxyl group (-0H) - in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group unsubstituted otherwise as defined above . The phrase "substituted alkoxy" refers to a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group otherwise substituted as defined above. The phrase "unsubstituted heterocyclyloxy" refers to a hydroxyl group (-0H) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of a heterocyclyl group unsubstituted otherwise as defined above. The phrase "substituted heterocyclyloxy" refers to a hydroxyl group (-0H) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of a heterocyclyl group otherwise substituted as defined above. The phrase "unsubstituted heterocyclyloxyalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted heterocyclyl group as defined above. The phrase "substituted heterocyclyloxyalkyl" refers to an unsubstituted heterocyclyloxyalkyl group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclyloxyalkyl group is linked to a non-carbon and not hydrogen atom as described above with respect to alkyl groups substituted or in which the heterocyclyl group of the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined above. The phrase "unsubstituted heterocyclylalkoxy" refers to an unsubstituted alkyl group as defined above in which a carbon bond or a hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound, and wherein another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to an unsubstituted heterocyclyl group as defined above. The phrase "substituted heterocyclylalkoxy" "refers to an unsubstituted heterocyclylalkoxy group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclylalkoxy group is bonded to a non-carbon and not hydrogen atom as described above with respect to substituted alkyl groups in which the heterocyclyl group of the heterocyclylalkoxy group is a substituted heterocyclyl group as defined above In addition, a heterocyclylalkoxy group also includes groups in which a carbon bond or a hydrogen bond to the The group alkyl may be substituted with one or more additional substituted or unsubstituted heterocycles Examples include but not limited to pyrid-2-ylmorpholin-4-ylmethyl and 2-methyl-3-yl-3-orpholin-4-ylethyl The phrases "arylaminoalkyl" "unsubstituted" refers to an unsubstituted alkyl group as defined above in which a carbon bond or a hydrogen bond is replaced by a bond to a nitrogen atom which binds to at least one unsubstituted aryl group as defined above The phrase "substituted arylaminoalkyl" refers to an unsubstituted arylaminoalkyl group as defined above except where either the alkyl group of the arylaminoalkyl group is a substituted alkyl group as defined above or the aryl group of the arylaminoalkyl group is a substituted aryl group except that the bonds to the nitrogen atom in all the arylaminoalkyl groups do not by themselves qualify all the arylaminoalkyl groups as they are being substituted., the substituted arylaminoalkyl groups include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and not hydrogen atom. The phrase "unsubstituted heterocyclylaminoalkyl" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom which binds to at least one heterocyclyl group replaced as defined above. The phrase "substituted heterocyclylaminoalkyl" refers to unsubstituted heterocyclylaminoalkyl groups as defined above in which the heterocyclyl group is a substituted heterocyclyl group as defined above and / or the alkyl group is a substituted alkyl group as defined above. The bonds to the nitrogen atom in all "the heterocyclylaminoalkyl groups do not by themselves qualify all the heterocyclylaminoalkyl" as they are being substituted. However, the substituted heterocyclylaminoalkyl groups include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon atom and not hydrogen. The phrase "unsubstituted alkylaminoalkoxy" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another The carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above. The phrase "substituted alkylaminoalkoxy" refers to unsubstituted alkylaminoalkoxy groups as defined above in which a bond to a carbon or hydrogen atom of the alkyl group linked to the oxygen atom which is bonded to the parent compound is replaced by one or more links to non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and / or if the hydrogen bonded to the amino group is bonded to a non-carbon and not hydrogen atom and / or the linked alkyl group the nitrogen of the amine is bonded to a non-carbon and not hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all alkylaminoalkoxy groups does not by itself qualify all groups as substituted alkylaminoalkoxy groups. The phrase "unsubstituted dialkylaminoalkoxy" refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another The carbon or hydrogen bond of the unsubstituted alkyl group is bonded to the nitrogen atom which is bonded to two similar or different unsubstituted alkyl groups as defined above. The phrase "substituted dialkylaminoalkoxy" refers to an unsubstituted dialkylaminoalkoxy group as defined above in which a bond to a carbon or hydrogen atom of the alkyl group linked to the oxygen atom to which it is bonded to the parent compound is replaced by one or more bonds to a non-carbon and not hydrogen atom as discussed above with respect to substituted alkyl groups and / or if one or more of the alkyl groups bonded to the nitrogen of the amine is attached to a non-carbon atom and not hydrogen as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all dialkylaminoalkoxy groups does not by itself qualify all groups as substituted dialkylaminoalkoxy groups. The term "protected" with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those indicated in the Protective Groups in Organic Síntesis, Greene, T.W.; Wuts, P.G. M., John Wiley & Sons, New York, NY, (3rd edition, 1999) which can be added or removed using the procedures indicated therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by the reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, format, acetate, trichloroacetate, and benzoyl trifluoroacetate. Examples of protected amine groups include, but are not limited to, amides such as formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemitium, dithio and aminothio acetals; and others. A "pharmaceutically acceptable salt" includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic amino acid or acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; ferrous alkaline metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine and triethanolamine. As salts of inorganic acids, the present invention includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the present invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, Benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the present invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid. In another aspect, the invention provides a method for modulating an inflammatory response and / or reducing cell adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and / or cell adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof. In one embodiment, the invention provides a method for treating a disorder related to inflammation in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. Inflammation and inflammatory responses can occur with several biological conditions. Examples of such biological conditions may include cancer, autoimmune diseases, asthma, allergies, eczema, microbial infections, traumatic injuries such as burns or cuts, lupus, arthritis, cardiovascular disease such as, but not limited to heart attacks and ischemic damage, bacterial infections and Respiratory viruses and other conditions associated with inflammatory responses. In another modality, the invention provides a method for treating a disorder related to cell adhesion in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. In another embodiment, the invention provides a method for decreasing cell adhesion molecules such as ICAM, VCAM, e-selectin, MMP-2 or MMP-9 levels in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The amount of the cell adhesion molecule is typically reduced in the subject after administration. In another embodiment, the invention provides a method for decreasing levels of circulating ICAM, VCAM, E-selectin, MMP-2 or MMP-9 in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. In another embodiment, the invention provides a method for decreasing circulating cell adhesion molecules in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. In yet another embodiment, the invention provides a method for monitoring the progression of a disease or treatment in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof and measuring the amounts of a molecule such as levels of ICAM, VCAM, E-selectin, MMP-2 or MMP-9 in the subject. In another aspect, the invention provides a method for monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one molecule of cell adhesion in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a salt. pharmaceutically acceptable of the tautomer, or a mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-selectin). Some such methods also include extracting a blood sample from the subject and then measuring the amount of at least one cell adhesion molecule in at least a portion of the sample. In another aspect, the invention provides a method for identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during or after the administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the compound. tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some modalities, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-selectin). Some such methods also include extracting a blood sample from the subject and then measuring the amount of at least one cell adhesion molecule in at least a portion of the sample. In some embodiments of any of the methods described herein, the subject is a patient with cancer. Structure I has the following formula Wherein, R1, R2, R3, and R4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN groups, -N02, -OH, -OR15, groups -NR16R17, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, (alkyl) (aryl) groups substituted and unsubstituted aminoalkyl, substituted and unsubstituted heterocyclylalkyl groups and -C (= 0) R groups 18, R5, R6, R7 and R8 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, groups -N02, -OH, -OR19, -NR20R21 groups, groups - SH,. -SR22, -S (= 0) R23 groups, -S (= 0) 2R24 groups, substituted and unsubstituted CN, amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, groups (alkyl) (aryl) substituted and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) R25 groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, groups substituted and unsubstituted alkoxyalkyl, aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups; R 12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH groups, alkoxy, aryloxy groups, -NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, groups substituted and unsubstituted alkylamino, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amino groups, -C (= 0) H groups, - C (= 0) -alkyl, groups -C (= 0) -aryl, groups -C (= 0) O-alkyl, groups -C (= 0) O-aryl, C (= 0) NH2, groups -C (= 0) H (alkyl), groups -C (= 0) NH (aryl, groups -C (= 0) N (alkyl ) 2, groups -C (= 0) (aryl) 2, groups -C (= 0) N (alkyl) (aryl), groups -C (= 0) -heterocyclyl, groups -C (= 0) NH (heterocyclyl) ), -C (= 0) -N (heterocyclyl) 2 groups, -C (= 0) - (alkyl) (heterocyclyl) groups, -C (= 0) -N (aryl) (heterocyclyl) groups, substituted heterocyclylaminoalkyl groups and unsubstituted, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups. R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted substituted groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, - C (= 0) H, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C ( = 0) NH (aryl), groups -C (= 0) (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), groups. substituted and unsubstituted aminoalkyl, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted heterocyclylaminoalkyl groups and unsubstituted, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups , substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; Rld and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -C (= 0) H groups, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups-C (= 0) NH (alkyl), groups -C (= 0) NH (aryl) , groups -C (= 0) (alkyl) 2, groups -C (= 0) N (aryl) 2, groups-C (= 0) (alkyl) (aryl), groups -C (= 0) 0-alkyl , C (= 0) 0-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted diarylaminoalkyl groups and unsubstituted, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, -C (= 0) -heterocyclyl groups, -C (= 0) -0-heterocyclyl groups, groups -C (= 0) NH (heterocycle), groups -C (= 0) -N (heterocyclyl) 2, groups -C (= 0) - N (alkyl) (heterocyclyl), groups -C (= 0) - N (aryl) (heterocyclyl), substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R18, R23, R24, and R25 can be the same or different or are independently selected from the group consisting of H, -NH2, -NH (alkyl) groups, -NH (aryl) groups, - (alkyl) groups, 2 groups - (aryl) 2, -N (alkyl) (aryl) groups, NH (heterocyclyl) groups, - (heterocyclyl) (alkyl) groups, -N (heterocyclyl) (aryl) groups, -N (heterocyclyl) 2 groups, groups substituted and unsubstituted alkyl, substituted and unsubstituted aryl groups, -OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, -NHOH groups, -N (alkyl) OH groups, -N (aryl) OH groups, -N (alkyl) -O-alkyl groups, -N (aryl) O-alkyl groups, N- (alkyl) O-aryl groups, and -N (aryl) O-aryl groups; and R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In some embodiments of the pharmaceutically acceptable salts of the compounds of the tautomers of the compounds of Structure I, at least one of R5, R6, R7 or R8 is selected from the group consisting of substituted and unsubstituted amidinyl groups, guanidinyl groups substituted and unsubstituted, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted (alkyl) (aryl) aminoalkyl groups and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted aryloxyalkyl groups and not substituted and substituted and unsubstituted heterocyclyloxyalkyl groups; OR19 groups in which R19 is selected from the group consisting of substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) H groups, -C (= 0) -aryl, -C (= 0) NH2-, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl), groups -C (= 0) N (alkyl) 2, groups C (= 0) N (aryl) 2, groups C (= 0) N (alkyl) (aryl) _, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, groups substituted and unsubstituted dialkylaminoalkyl, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, groups (heterocyclic) ) (alkyl) substituted and unsubstituted aminoalkyl, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, heterocyclyloxyalkyl groups ilo substituted and unsubstituted; the groups -NR20R21 wherein R20 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; the groups - NR20R21 where R21 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, -C (= 0) H groups, -C (= 0) -aryl groups, -C (= 0) NH2, -C groups (= 0) H (alkyl), groups -C (= 0) NH (aryl), groups -C (= 0) N (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), -C (= 0) O-alkyl groups, -C (= 0) O-aryl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, dialkylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted alkoxyalkyl groups and unsubstituted, substituted and unsubstituted aryloxyalkyl groups, substituted heterocyclylalkyl groups and not sub established; substituted and unsubstituted heterocyclyloxyalkyl groups; and -C (= 0) R25 wherein R25 is selected from the group consisting of H, -NH2 groups, NH (alkyl), -NH (aryl) groups, - (alkyl) 2 groups, -N (aryl) 2 groups, -N (alkyl) (aryl) groups, NH (heterocyclyl) groups, - (heterocyclyl) groups (alkyl ), -N (heterocyclyl) (aryl) groups, -N (heterocyclyl) 2 groups, substituted and unsubstituted aryl groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted heterocyclyl groups. In one embodiment, the invention relates to a pharmaceutically acceptable salt of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -quinolin-2 (1H) ) -one (Compound 1) or a tautomer thereof. In some embodiments, the salt is selected from the group consisting of tartrate, malate, lactate, bis-acetate, citrate, bismethylate and bishydrochlorate. In some specific embodiments, the compound of Structure I is a lactate salt of 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (ÍH) -one or a tautomer thereof. In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. In some embodiments, at least one of R12 and R13 is H, and in other embodiments, both R12 and R13 are H. In some embodiments, R1 is selected from the group consisting of F, Cl, substituted and unsubstituted alkoxy groups, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkoxy groups, substituted and unsubstituted arylaminoalkoxy groups, substituted and unsubstituted dialkylaminoalkoxy groups, substituted and unsubstituted diarylaminoalkoxy groups, and (alkyl) (aryl) groups substituted and unsubstituted aminoalkoxy. In some embodiments, R1 is F and R2, R3, R4, R5 and R8 are all H, and one of R6 or R7 is H. In some embodiments, at least one of R5, R6, R7, and R8 is a group substituted or unsubstituted heterocyclyl. In still other embodiments, at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom. In still other embodiments, at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran and tetrahydropyran. In still other modalities, at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group. In still other embodiments, at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group which comprises at least one O or N atom. In still other embodiments, one of R6 and R7 is a substituted heterocyclyl group or unsubstituted and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran and tetrahydropyran. In yet other particular embodiments, one of R6 or R7 is selected from the group consisting of substituted and unsubstituted morpholine groups, and substituted and unsubstituted piperazine groups. In some such embodiments, one of R6 or R7 is a piperazine N-oxide or is a substituted N-alkyl piperazine. In still other embodiments, at least one of and in some embodiments one of Rd or R7 is selected from the group consisting of -NR20R21 groups wherein R20 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; and groups -NR20R21 wherein R21 is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, heterocyclylalkyl groups substituted and unsubstituted, and substituted and unsubstituted heterocyclyloxyalkyl groups. In yet another embodiment, R1 is selected from the group consisting of H and F. In yet another embodiment, the compounds and their corresponding salts and tautomers are provided in the following two subsequent tables. The. synthesis of these compounds is described in the patent of the United States of North America NO. 6,605,617, U.S. Patent Application Publication No. 2004/0092535, U.S. Patent Application Publication No. 2004/0220196 as are various kinase assay procedures. Each of these references is, therefore, incorporated herein by reference in its entirety and for all purposes as indicated in its entirety.

Table of example compounds 146 4- [(3S) -l-azabicyclo [2 .2.2] oct-3-ylamino] -476 3- (lH-benzimidazol-2-yl) -6-fluoro-7- [(2-methylpropyl) amino] quinolin-2 (1H) -one 147 4- [(3R) -l-azabicyclo [2 .2.2] oct-3-ylamino] -401 3- (lH-benzimidazol-2-yl) -5- methylquinolin-2 (1H) -one 148 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -532 6- (2,4-dichlorofenyl) -3- (3H-) imidazo [4, 5-b] pyridin-2-yl) uinolin-2 (1H) -one 149 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] - 531 3- (1H-benzimidazol-2-yl) -6- [3- (trifluoromethyl) phenyl] quinolin-2 (1H) -one 150 3- (1H-benzimidazol-2-yl) -4- 305 (dimethylamino) quinolin-2 (lH) -one 151 4-hydroxy-3- (lH-imidazo [4, 5-f] quinolin-2-yl-yl) quinolin-2 (1 H) -one 152 4-hydroxy-3 - (1H-imidazo [4, 5-b] pyridin-2, 279 yl) quinoline-2 (1H) -one 153 4- [4- [(3R) -l-azabicyclo [2 .2 .2] acid oct -3,525-ylamino] -3- (lH-benzimidazol-2-yl) -5- fluoro-2-oxo-l, 2-dihydroquinolin-6-yl] benzoic 205 4- ( { [4- ( aminomethyl) fenyl] methyl.} amino) -6- 529 chloro-3- [5- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) -one 206 6 -cloro-4-. { [2- (methylamino) ethyl] amino} -3- 467 [5- (4-methyl-piperazin-1-yl) -1H-benzimidazol-2-yl] -quinolin-2 (1 H) -one 207 6-chloro-3- [5- (methyl-piperazin-1-yl) -1H- 550 benzimidazol-2-yl] -4-. { [3- (4- methyl-piperazin-1-yl) propyl] amino} quinolin-2 (1H) -one 208 6-chloro-3- [5- (4-methyl-piperazin-1-yl) -1H-583-benzimidazol-2-yl] -4-. { [1- (f -methylmethyl) piperidin-4-yl] amino} quinolin-2 (HH) -one 09 6-chloro-3- [5- (4-methylpiperazin-1-yl) -1H-507 benzimidazol-2-yl] -4- [(2-pyrrole idin-1-ylethyl) ) amino] quinolin-2 (lH) -one 10 6-chloro-3- [5- (4-methyl-piperazin-1-yl) -lH-479-benzimidazol-2-yl] -4- (pyrrolidin-3-ylamino) ) indium in- 2 (ÍH) -one 11 6-chloro-3- [5- (4-methylpiperazin-1-yl) -1H-493 benzimidazol-2-yl] -4- (piperidin-4-yl) quinolin-2 (1H) -one Table of additional example compounds 446 4 - [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -518.6 3- (lH-benzimidazol-2-yl) -7-. { [2- (Ethylamino) ethyl] amino} -6- fluoroquinolin-2 (HH) -one 447 4 - [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -516.6 3- (lH-benzimidazol-2-yl) -6-fluoro -7 - [(2-pyrrolidin-1-ylethyl) amino] quinolin-2 (1H) -one 448 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] - 530.7 3- (lH-benzimidazol-2-yl) -6-fluoro-7- [(2-piperidin-1-ylethyl) amino] guinolin-2 (lH) -one 449 4 - [(3R) -l-azabicyclo [2.2. 2] oct-3-ylamino] - 504.6 3- (1H-benzimidazol-2-yl) -7-. { [3- (dimethylamino) propyl] amino} 6- fluoroguinolin-2 (HH) -one 50 N- (2- { [4- [(3R) -l-azabicyclo [2.2.2] oct-3- 504.6 ylamino] -3- (lH-benzimidazole- 2-yl) -6- f luoro-2-oxo-l, 2-dihydroquinolin-7-yl] amino.} Ethyl) acetamide 451 N-. { l- [4- [(3R) -l-azabicyclo [2.2.2] oct-3, 584.6 ylamino] -3- (lH-benzimidazol-2-yl) -6- f luoro-2-oxo-l, 2 -dihydroquinolin-7-yl] pyrrolidin-3-yl} -2, 2,2- trifluoroacetamide 452 3-. { [4- [(3R) -l-azabicyclo [2.2.2] oct-3,772.5-ylamino] -3- (lH-benzimidazol-2-yl) -6-fluoro-2-oxo-l, 2-dihydroquinoline- 7- il] amino} propanonitrile 453 N- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -43.6.5 3- (lH-benzimidazol-2-yl) -6-fluoro-7- [(2-hydroxyethyl) amino] ] guiñol in- 2 (ÍH) -one 454 N- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -777.6 3- (lH-benzimidazol-2-yl) -6-fluoro- 7 - [(2-methoxyethyl) amino] quinine lin-2 (1H) -one 455 N - [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -503.6 3- (1H-benzimidazol-2-yl) -6-fluoro-7- (3-hydroxypiperidin-1-yl) quinolin-2 (1H) -one 456 N- [(3S) -l-azabicyclo [2.2.2] ] oct-3-ylamino] - 504.6 3- (1H-benzimidazol-2-yl) -7 - [[2- (dimethylamine) ethyl] (methyl) amino] -6- f luoroguinolin-2 (H) -one 470 N - [(3S) -l- azabicyclo [2.2.2] oct-3-ylamino] -516.6 3- (lH-benzimidazol-2-yl) -7 - [(3R) -3- (dimethylamino) pyrrolidin-1-yl] -6- f luoroguinolin- 2 (1H) -one 471 N-. { l- [4- [(3S) -l-azabicyclo [2.2.2] oct-3, 584.6 ylamino] -3- (lH-benzimidazol-2-yl) -6-fluoro-2-oxo-l, 2- dihydroguinolin-7-yl] pyrrolidin-3-yl} -2, 2,2- trifluoroacetamide 472 N - [(3S) -l-azabicyclo [2.2.2] oct-3-ylamino] -501.6 7-azepane-l-yl-3- (lH-benzimidazole-2-yl) il) -6- f luoroguinolin-2 (ÍH) -one 73 N- [(3S) -l-azabicyclo [2.2.2] oct-3-ylamino] -503.6 3- (lH-benzimidazol-2-yl) - 6-fluoro-7- (3-hydroxypiperidin-1-yl) quinolin-2 (HH) -one 74 3-. { [4- [(3S) -l-azabicyclo [2.2.2] oct-3,772.5-ylamino] -3- (lH-benzimidazol-2-yl) -6-fluoro-2-oxo-l, 2-dihydroquinoline- 7- il] amino} propanitrile 75 N - [(3S) -l-azabicyclo [2.2.2] oct-3-ylamino] -469.5 3- (lH-benzimidazol-2-yl) -6-fluoro-7- (1H-pyrrole-1- il) quinolin-2 (ÍH) -one 4-. { [(4-amino-2-methylpyrimidin-5,458.5 il) methyl] amino} -3- (lH-benzidazol-2-yl) 6,7-dimethoxyquinoline-2 (1H) -one 3- (lH-benzimidazol-2-yl) -4- { [2- (5-fluoro-498.5 lH-indol-3-yl) ethyl] amino.}. -6,7-dimethoxyquinoline-2 (1 H) -one 4- { [2- (4-aminofenyl) ethyl] amino.} -3- (1 H- 456.5 benzimidazol-2-yl) -6,7-dimethoxyquinolin-2 (lH) -one 4 - [(3R) -1 l-azabicyclo [2.2.2] oct-3-ylamino] -471.6 3- (lH -benzimidazol-2-yl) -7-morpholin-4-ylguinolin-2 (H) -one 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -430.5 3- (5, 6-difluoro-lH-benzimidazol-2-yl) -6,7-dimethoxy-guiyolin-2 (H) -one 3-amino-4- [4- [(3R) -l-azabicyclo [2.2.2] oct- 535.6 3-ylamino] -3- (lH-benzimidazol-2-yl) -1-oxo-1,2-dihydroguinolin-7-yl] methyl benzoate 4- [(3R) -l-azabicyclo [2.2.2] oct -3-ylamino] - 540.7 3- (1H-benzimidazol-2-yl) -7- [4- (methylsulfonyl) phenyl] wink lin-2 (1H) -one 509 N - [(3R) -l-azabicyclo [2.2.2] oct-3 -amino] - 487.0 3- (lH-benzimidazol-2-yl) -6-chloro-7- (1H-imidazol-1-yl) guinolin-2 (lH) -one 510 N - [(3R) -l- azabicyclo [2.2.2] oct-3-ylamino] -459.6- 3- (lH-benzimidazol-2-yl) -7 - [(3H-hydroxypropyl) amino] guinolin-2 (1 H) -one 511 N- [( 3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -526.7 3- (lH-benzimidazol-2-yl) -7-. { [3- (2-oxopyrrolidin-1-yl) propyl] amino} quinolin- 2 (lH) -one 512 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -484.6 3- (lH-benzimidazol-2-yl) -7- (4-methylpiperazine -1-yl) quinolin-2 (1 H) -one 513 4- [4- [(3 R) -l-azabicyclo [2.2.2] oct-3-487.6 ylamino] -3- (lH-benzimidazol-2-yl) ) -2-oxo-1,2-dihydroquinolin-7-yl] benzonitrile 514 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] - 530.6 3- (1H-benzimidazol-2-yl) -7- [2- (trifluoromethyl) phenyl] quinolin-2 (1H) -one 4- [(3R) -l-azabicyclo [2.2.2] oct-3- ilamino] - 506.6 3- (lH-benzimidazol-2-yl) -7- (1,3-benzodioxo-5-yl) guiñol in- 2 (1H) -one 523 Acid 4- [4- [(3R) - l-azabicyclo [2.2.2] oct-3, 549.6-ylamino] -3- (lH-benzimidazol-2-yl) -7- (imethylamino) -2-oxo-l, 2-dihydroguinolin-6-yl] benzoic 524 4- [4- [(3R) -l-azabicyclo [2.2.2] oct-3, 572.6 ylamino] -3- (lH-benzimidazol-2-yl) -7- (1H-imidazol-1-yl) acid -2-oxo-l, 2-dihydroguinolin-6-yl] benzoic 525 4 - [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] - 530.4 3- (1H-Benzimidazol-2-yl) -7-fluoro-6-iodoquinolin-2 (1H) -one 526 4- [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] -558.6 3- (1H-Benzimidazol-2-yl) -7-fluoro-6- [4- (methylsulfonyl) f-enyl] guinolin-2 (1H) -one 527 4- [4- [(3R) -l-azabicyclo [ 2.2.2] oct -3,523.6-ylamino] -3- (lH-benzimidazol-2-yl) -7- f luoro-2-oxo-l, 2-dihydroquinolin-6-yl] benzamide 528 6 (4-acetyl) enyl) -4- [(3R) -1- 522.6 azabicyclo [2.2.2] oct-3-ylamino] -3- (1H-benzimidazol-2-yl) -7- (fluoroquinolin-2 (lH) -one 605 6-chloro-3- (5-morpholin-4-yl-lH-516. 0-benzimidazol-2-yl) -4- [3- (2-pyridin-2-propyl) amino] guiolinin-2- (1H) -one 606 6-chloro-3- (5-morpholin-4-yl-lH-473,9-benzimidazol-2-yl) -4- (pyridin-4-ylamino) guinolin-2- (1H) -one 607 6 -chloro-3- (5-morpholin-4-yl-lH-601. 1-benzimidazol-2-yl) -4- ( { [6- (piperidin-3-ylmethoxy) pyridin-3-yl] methyl} amino) guinolin-2- (OH) -one 608 6-chloro-3- (5-morpholin-4-yl-lH-473,9-benzimidazol-2-yl) -4- (pyridin-2-ylamino) guinolin-2 (ÍH) -one 609 Acid l- [4- [(3R) -l-azabicyclo [2 .2.2] oct-3-548.1 ylamino] -3- (lH-benzimidazol-2-yl) -6-chloro-2-oxo-l, 2-dihydroguinolin-7-yl] piperidine-4-carboxylic acid 610 L- [4- [(3R) -l-azabicyclo [2.2.2] oct -3,513 acid. 6-ylamino] -3- (lH-benzimidazol-2-yl) -2-oxo-1,2-dihydroguinolin-7-yl] piperidin-4-carboxylic acid 11 3- [4- [(3S) -l-azabicyclo] [2 .2 .2] oct-3- 506. 6-ylamino] -3- (lH-benzimidazol-2-yl) -2-oxo-1,2-dihydroguinolin-7-yl] benzoic 619 6- (4- acetylf-enyl-4- [(3R) -1-522.6 azabicyclo [2.2.2] oct-3-ylamino] -3- (1H-benzimidazol-2-yl) -5-fluoroquinolin-2- (lH) -one 620 4- [4- [(3R) -l-azabicyclo [2.2.2] oct -3,338.6-ylamino] -3- (lH-benzimidazol-2-yl) -5- fluoro-2-oxo-l, 2- Methyl dihydroquinolin-6-yl] benzoate 621 3-amino-4- [4 - [(3R) -l-azabicyclo [2.2.2] oct-553.6 3-ylamino] -3- (lH-benzimidazol-2-yl) ) -5- fluoro-2-oxo-l, 2-dihydroguinolin-6-yl] methyl benzoate 622 3- [4 - [(3R) -l-azabicyclo [2.2.2] oct-3 538.6 ylamino] - 3- (lH-benzimidazol-2-yl) -5- fluoro-2-oxo-l, 2-dihydroguinolin-6-yl] methyl benzoate 23 4 - [(3R) -l-azabicyclo [2.2.2] oct -3-ylamino] -494.6 3- (lH-benzimidazol-2-yl) -5-f luoro-6- (2-methylphenyl) guinolin-2 (1H) -one 24 4 - [(3R) -l-azabicyclo [2.2.2] oct-3-ylamino] - 508.6 3- (lH-benzimidazol-2-yl) -6- (2-ethylfenyl) -5-f luoroguinolin-2 (ÍH) -one 2 (lH) -one 782 3- (5-chloro-lH-benzimidazol-2-yl) -6-methyl-422.9 4 - [(piperidin-4-ylmethyl) amino] quinolin-2 (lH) -one 783 4 - [(4-aminocyclohexyl) amino] -3- (5-chloro-422.9 lH-benzimidazol-2-yl) -6-methylquinolin-2 (lH) -one 784 3- (5-chloro-lH-benzimidazole-2 -yl) -6-methyl-382.9 4-. { [2- (methylamino) ethyl] amino} quinolin- 2 (lH) -one 85 3- (5-chloro-lH-benzimidazol-2-yl) -6-methyl-394.9 4- (pyrrolidin-3-ylamino) quinolin-2 (H) -one 86 3- (5-chloro-lH-benzimidazol-2-yl) -6-methyl-422.9 4- [(piperidin-2-ylmethyl) amino] guinolin-2 (lH) -one 87 4 - [(3S) -l-azabicyclo [2.2.2] oct-3-ylamino] - 434.9 3- (5-chloro-lH-benzimidazol-2-yl) -6-methyl-lyrolin-2 (IH) -one 4- [(3R) -l-azabicyclo [ 2.2.2] oct-3-ylamino] - 434.9 3- (5-chloro-lH-benzimidazol-2-yl) -6-methylquinoline-2 (1H) -one 947 6-chloro-3- (7-morpholin-4-yl-lH-466.0 benzimidazol-2-yl) -4- [(3S) -pyrrolidin-3-ylamino] guinolin-2 (ÍH) -one 948 4- amino-7-fluoro-3- [5- (4-methylpiperazin-393.4 1-yl) -lH-benzimidazol-2-yl] guinolin-2 (lH) -one 949 4-amino-3-. { 6- [(2,6-Dimethyl-piperazin-1-417.5 il) carbonyl] -lH-benzimidazol-2-yl} guinolin-2 (1H) -one 950 4-amino-3- (5- { (2S, 2R) -2- 451.5 [(dimethylamino) methyl] -5-methylmorpholin-4-yl} -lH-benzimidazol-2-yl) -5- fluoroquinolin-2 (1H) -one 951 6-chloro-3- (5-morpholin-4-yl-lH-466.0 benzimidazol-1-yl) -4- [( 3S) -pyrrolidin-3-ylamino] quinolin-2 (1H) -one 952 4-amino-3- (5- { (2S, 5S) -2- 451.5 [(dimethylamino) methyl] -5-methylmorpholin-4-yl} -lH-benzimidazol-2-yl) -5- fluoroquinolin-2 (1H) -one 53 4-amino- (1H-benzimidazol-2-yl) -6-403.5 [methyl (1-methylpiperidin-yl) amino] quinoline -2 (ÍH) -one 971 6-bromo-3- (6-chloro-5-fluoro-lH-477.7 benzimidazol-2-yl) -4- [(3R) -pyrrolidin-3-ylamino] -quinolin-2 - (ÍH) -one 972 6-bromo-3- (6-chloro-5-fluoro-lH-505.8 benzimidazol-2-yl) -4- [(piperidin-2-ylmethyl) amino] quinolin-2- (OH) ) -one 973 4- [(3S) -l-azabicyclo [2.2.2] oct -3,517.8-ylamino] -6-bromo-3- (6-chloro-5-fluoro-lH-benzimidazol-2-yl) -guinolin-2- (OH) -one 974 4- [(3R) -l-azabicyclo [2.2.2] oct -3,517.8-ylamino] -6-bromo-3- (6-chloro-5-fluoro-lH - benzimidazol-2-yl) -guinolin-2- (OH) -one 975 4- [(3R) -l-azabicyclo [2.2.2] oct-3-483.4 ylamino] -6-bromo-3- (6- fluoro-lH-benzimidazol-2-yl) -guinolin-2- (1 H) -one 976 4- [(3R) -1-azabicyclo [2.2.2] oct-3- 438.9 ylamino] -6-chloro-3- (6-fluoro-lH-benzimidazol-2-yl) -guinolin-2- (lH) -one 977 4-amino-6- [bis (cyclohexylmethyl) amino] -3- 512.7 (6,7-dimethyl-lH- b enimidazol-2-yl) guinolin-2- (1H) -one 978 4-amino-6- [bis (cyclohexylmethyl) amino] -3- 512.7 (5,6-dimethyl-lH-benzimidazol-2-yl) guinolin- 2- (ÍH) -one 1018 6-chloro-3- (6-. { 3- 507.1 [(dimethylamino) methyl] pyrrolidin-1-yl} -1H- benzimidazol-2-yl) -4- [(3S) -pyrrolidin-3-yla) -quinolin-2 (1H) -one 1019 4-. { [(2R) -2-aminobutyl] amino} -6-chloro-3- 509.1 (6- { 3- [(dimethylamino) methyl] pyrrolidin-1-yl}.-LH-benzimidazol-2-yl) quinolin-2 (1 H) -one 1020 6- chlorine-3- (6- { 3- 521.1 [(dimethylamino) ethyl] irolidin-1-yl} -1H- benzimidazol-2-yl) -4-. { [(3S) -1- methylpyrrolidin-3-yl] amino) quinolin-2 (H) -one 1021 6-chloro-3- (6-. {3-3 535.1 [(dimethylamino) methyl] pyrrolidin-1-yl} -1H- benzimidazol-2-yl) -4- [(1-methylpyrrolidin-4-yl) amino] quinolin-2 (lH) -one 1022 3- (lH-benzimidazol-2-yl) -6-chloro-4 - 408.9 . { [(3S) -piperidin-3-ylmethyl] amino} uiñolin-2 (lH) -one 1023 3- (lH-benzimidazol-2-yl) -6-chloro-4- 408.9. { [(3S) -piperidin-3-yl] ethyl] amino} guinolin-2 (lH) -one 1125 4-amino-5-fluoro-3- (6- { [3- (4-4,4-methyl-piperazin-1-yl) -propyl] -amino} -1H-benzimidazole -2-yl) quinolin-2 (lH) -one 1126 4-amino-5-fluoro-3- (6-. {Methyl} [3- (4,464,6-methylpiperazin-1-yl) propyl] min .}. -1 H -benzimidazol-2-yl) quinolin-2 (H) -one 1127 N- [2- (4-amino-5-fluoro-2-oxo-l, 2- 366. 4 dihydroguinolin-3- il) -lH-benzimidazol-6-yl) N-methylacetamide 1128 4-amino-6-fluoro-3- (5- { [(2R) -2- 475. (pyrrolidin-1-imethyl) pyrrolidin-1-yl] carbonyl} -lH-benzimidazol-2-yl) guinolin-2 (1H) -one 1129 4-amino-3- (1H-benzimidazol-2-yl) -5- 320. 4 (ethylamino) guinolin-2 (1H) -one 1130 4-amino-3 ~. { 5- [(2R) -2, 4-dimethylpiperazine-407. 5 1 -yl] -lH-benzimidazol-2-yl} -5- fluorguinolin-2 (1 H) -one 1131 4-amino-5-fluoro-3-. { 5- [(2R) -2.4-393. 4-dimethylpiperazin-1-yl] -lH-benzimidazol-2-yl} -5-fluorguinolin-2 (1H) -one 1132 4-amino-3-. { 5- [(2R) -4-Cyclobutyl-2-447. 5-methylpiperazin-1-yl] -lH-benzimidazol-2-yl} -5-fluorguinolin-2 (HH) -one 1147 N- [2- (4-amino-5-fluoro-2-oxo-l, 2- 451.5-dihydroquinolin-3-yl) -lH-benzimidazole-6- il] -N-methyl-2-morphin-4-ylacetamide 1148 N- [2- (4-amino-5-fluoro-2-oxo (3- 492.6 didroquinolyl) benzimidazol-6-yl] -N-methyl - 2-morphin-4-ylacetamide 1149 4-amino-5-fluoro-3- (6-methyl-1H-309 .3-benzimidazol-2-yl) quinolin-2 (lH) -one 1150 4-amino-3- [5- (4-ethylpiperazin-1-yl) 1H-403.5-benzimidazol-2-yl] -5-methyl-guolinolin-2 (1H) -one 1151 4-amino-3-. {6- [4-methyl-piperazin- l- 389. 5-yl) methyl] -lH-benzimidazol-2-yl) uinolin-2 (lH) -one 1152 4-amino-3- [6- (1,4-diazepane-l-yl) -1H- 393. 4-benzimidazazol-2-yl] -5-fluoroquinolin-2 (lH) -one 1153 4-amino-5-fluoro-3- [6- (4-methyl-l, 4- 407.5 diazepane-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (1H) -one 1154 3- [6- (4-acetylpiperazain-1-yl) -1H-421.4 benzimidazol-2-yl] -4-amino-5-fluoroquinoline -2 (ÍH) -one In yet another embodiment, the compound of Structure I is a compound of Structure II, where Structure II has the following formula: II Where A is a group which has one of the following Structures: Where Ra is selected from H or straight or branched chain alkenyl groups having from 1 to 6 carbon atoms. In some embodiments, where the compound of Structure I is a compound of Structure II, R is a methyl group, and the compound of Structure II is a compound of Structure IIA In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the substrate, and the salt is a lactate salt. In some embodiments, where the compound of Structure I is a compound of Structure II, Ra is H, and the compound of Structure II is a compound of Structure IIB ? B In some modalities, where the compound of the Structure I is a compound of Structure II, Ra is a methyl group, and the compound of Structure II is a composite of the IIC Structure pc. Compounds of any of the embodiments can be used to prepare medicaments or pharmaceutical formulations for use in any of the methods of the invention. Pharmaceutical formulations for use with the invention can include any of the compounds, tautomers, or salts of any of the embodiments described above in combination with a pharmaceutically acceptable carrier such as those described herein. The present invention also provides compositions which can be prepared by mixing one or more compounds of the present invention, or tautomers of pharmaceutically acceptable salts thereof, or mixtures thereof with carriers, excipients, binders, pharmaceutically acceptable diluents or the like for treat or improve disorders related to tumors with metastases. The compositions of the inventions can be used to create formulations for use in any of the methods of the invention. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The present compositions can be formulated by various routes of administration, for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection. The following dosage forms are given by the exemplary form and should not be constructed to limit the present invention. For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelatin capsules and oval tablets (Caplet®) are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the present invention, pharmaceutically acceptable salts, tautomers, or mixtures thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides . Optionally, the oral dosage forms may contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cytosine. , a disintegrating agent, binders, thickeners, buffers, flavoring agents or perfuming agents. The tablets and pills can be further treated with suitable coating materials known in the art. Liquid dosage forms for oral administration may be in the form of emulsions, syrups, suspensions and pharmaceutically acceptable solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments can be prepared as suspensions or liquid solutions using a sterile liquid, such as, but not limited to, an oil, water, alcohol, and combinations thereof. The pharmaceutically suitable surfactants, suspending agents, emulsifying agents, can be added for oral or parental administration. As indicated above, the suspensions may include oils. Such oil includes, but is not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension preparation may also contain fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly (ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations. For nasal administration, the pharmaceutical formulations and medicaments may be a spray or aerosol containing an appropriate solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation can include compressed air, nitrogen, carbon dioxide, or low boiling solvent based on hydrocarbon. Injectable dosage forms generally include aqueous suspensions or suspensions of oil which can be prepared using a suitable dispersing agent or wetting agent and a suspending agent. The injectable forms may be in the solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Solvents or acceptable vehicles include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, the sterile oils can be used as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile oil, which includes natural or synthetic oils, fatty acids, di- or tri-glycerides. For injection, the pharmaceutical formulation and / or medicament may be a suitable powder for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations thereof. For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of the compound in the intestines, sigmoidal and / or rectus flexure. Rectal suppositories are prepared by mixing one or more compounds of the present invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable carriers, for example, cocoa butter or polyethylene glycol, which occur in a solid phase at storage temperatures. normal, and present in a liquid phase at those temperatures suitable for releasing a drug within the body, such as in the rectum. The oils can also be used in the preparation of formulations of the soft gelatine type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols can be used in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methylcellulose, hydroxypropylcellulose or carboxymethylcellulose, as well as buffers. and conservatives. In addition to those representative dosage forms • described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present invention. Such excipients and carriers are described, for example, in "Remington Pharmaceutical Sciences" Mack Pub. Co. , New Jersey (1991), which is incorporated herein by reference in its entirety for all purposes as fully indicated herein. The formulations of the invention can be designed to be short acting, fast releasing, long acting, and sustained release as described above. In this way, the formulations can also be formulated for controlled release or for slow release. The present compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a storage and / or prolonged delivery effect. Thus, the pharmaceutical formulations and medicaments can be compressed into granules or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as Stent. Such implants may employ known inert materials such as silicones and biodegradable polymers. Specific doses can be adjusted depending on disease conditions, age, body weight, general health conditions, sex and diet of the subject, dose ranges, routes of administration, rate of excretion, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the limits of routine experimentation and therefore, are well within the scope of the present invention. An effective dose therapeutically may vary depending on the route of administration and dosage form. The preferred compound or compounds of the present invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the proportion of doses between the toxic and therapeutic effects which can be expressed as the ratio between LD5o and ED50. The LD50 is the lethal dose for 50% of the population and the ED50 is the therapeutically effective dose in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in cultures of animal cells or experimental animals. The pharmaceutical formulations and medicaments according to the invention include the compound of Structure I or the tautomer, salts or mixtures thereof in combination with a pharmaceutically acceptable carrier. In this way, the compounds of the invention can be used to prepare pharmaceuticals and pharmaceutical formulations. Such medicaments and pharmaceutical formulations can be used in any of the treatment methods described herein. The compounds and formulations of the present invention are particularly suitable for use in combination therapy. Kinase inhibitors for use as anticancer agents together with the methods or compositions of the present invention include inhibitors of epidermal growth factor receptor (EGFR) kinases such as small molecule quinazolines, for example gefitinib (U.S. Pat. of North America 5457105, U.S. Patent 5616582 and U.S. Patent 5770599), ZD-6474 (Application WO 01/32651), Erlotinib (Tarceva®, U.S. Patent 5,747,498 and application WO 96/30347), and lapatinib (U.S. Patent 6,727,256, and application 02/02552). Kinase inhibitors for use as anticancer agents together with the methods of compositions of the present invention also include inhibitors of the vascular endothelial growth factor receptor (VEGFR) receptor kinase inhibitor such as, but not limited to SU-11248 (application WO 01/60814), SU 5416 (United States of America 5,883,113 and application 99/61422), SU 6668 (United States of America 5,883,113 and application WO 99/61422), CHIR-258 (Patent United States of America 6,605,617 and United States of America 6,774,237), vatalanib or PTK-787 (United States of America 6,258,812), VEGF-Trap (application WO 02/574), B43-Genistein (application WO-09606116), fenretinide (retinoic acid-p-hydroxyphenylamine) (U.S. Patent 4,323,581), IM-862 (application WO 02/62826), bevacizumab or Avastin® (application WO 94/10202), KRN- 951, 3- [5- (metilsu lfonylpiperazin methyl) -indolyl] -quinolone, AG-13736"y_ AG-13925, pyrrole [2, lf] [1,2,4] triazines, ZK-304709, Veglin®, VMDA-3601, EG-004, CEP- 701 (U.S. Patent 5,621,100) and Cand5 (application WO 04/09769). The compounds of the invention can be used to treat a variety of subjects. Suitable subjects include animals such as mammals and humans. Suitable mammals include, but not limited to, primates such as, but are not limited to lemurs, apes and monkeys; rodents such as rats, mice, and coballos; rabbits and hares; cows; horses; pigs goats sheep; marsupials; and carnivores such as felines, canines, and ursines. In some modalities, the subject or patient is a human. In other embodiments, the subject or patient is a roder such as a mouse or rat. In some embodiments, the subject or patient is an animal other than a human and in some such modalities, the subject or patient is a mammal other than a human. Purification and Characterization of Compounds The compounds of the present invention are characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a Separation Module 2690 (Milford, Massachusetts). The analytical columns are Alltima C-18 reverse phase, 4.6 x 250 mm Alltech (Deerfield, Illinois). An elution gradient is used, typically starting with 5% acetonitrile / 95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contain 0.1% trifluoroacetic acid (TFA). The compounds are detected by absorption of ultraviolet (UV) light at either 220 or 254 nm. The HPLC solvents are from Burdick and Jackson (Muskegan, Michigan), or Fisher Scientific (Pittsburg, Pennsylvania). In some cases, purity is evaluated by thin layer chromatography (TLC) using glass or plastic reinforced silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. The results of the TLC are easily detected visually under ultraviolet light, or by using well-known iodine vapor and various other staining techniques. The mass spectrometric analysis is performed in one of two LCMS instruments: a Waters System (Alliance HT HPLC and a mass spectrometer Micromass ZQ; column: Eclipse XDB-C18, 2.1 x 50 mm; solvent system: 5-95% acetonitrile in water with 0.05% TFA, flow rate 0.8 ml / minute, molecular weight range 150-850, cone voltage 20 V, column temperature 40 ° C) or a Hewlett Packard system (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1 x 50 mm; Solvent system: 1-95% acetonitrile in water with 0.05% TFA, flow rate 0.4 ml / minute, molecular weight range 150-850; Cone voltage 50 V , column temperature 30 ° C). All masses are reported as those of protonated progenitor ions. The GCMS analysis is performed on a Hewlett Packard instrument (HP6890 series gas chromatograph with a mass selective detector 5973, injector volume: 1 μl, initial column temperature, 50 ° C, final column temperature: 250 ° C; ramp: 20 minutes, gas flow rate: 1 ml / minute, 5% phenyl methyl siloxane column, model #HP 190915-443, Dimensions: 30.0 x 25 μm x 0.25 μm). Preparative separations are performed using either a Flash 40 and KP-Sil, 60a chromatography system (Biotage, Charlottesville, Virginia), or by HPLC using a C-18 reverse phase column. Typical solvents used for the Biotage Flash 40 system are dichloromethane, methanol, ethyl acetate, hexane and triethylamine. The typical solvents used for reverse phase HPLC are varied concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

Synthesis of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one A. Synthesis of 5- (4-methyl-piperazin-1-yl) -2- nitroaniline Procedure A -Chloro-2-nitroaniline (500 g, 2898 moles) and 1-methylpiperazine (871 g, 8.693 moles) are placed in a 2000 ml flask fixed with a condenser and purged with N2. Place the flask in an oil bath at 100 ° C and heat until the 5-chloro-2-nitroaniline is completely reacted (typically overnight) as determined by HPLC. After the HPLC confirms the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture is emptied directly (still hot) into 2500 ml of water at room temperature with mechanical stirring. The resulting mixture is stirred until it reaches ambient temperatures and then filtered. The yellow solid of this obtained form is added to 1000 ml of water and it is dried for 30 minutes. The resulting mixture is filtered, and the resulting solid is washed with TBME (500 ml, 2X) and then dried under vacuum for one hour using a rubber press. The resulting solid is transferred to a drying tray and dried in a vacuum oven at 50 ° C to a constant weight to yield 670 g (97.8%) of the title compound as a yellow powder. Procedure B 5-Chloro-2-nitroaniline (308.2 g, 1.79 moles) is added to a fixed 4-neck, 5000 ml round bottom flask with an overhead stirrer, condenser, gas inlet, addition funnel, and probe of thermometer. The flask is then purged with N2. 1-Methylpiperazine (758.1 g, 840 ml, 7.57 mol) and 200 test ethanol (508 ml) are added to the reaction flask with stirring. The flask is again purged with N2 and the reaction is maintained under N2. The flask is heated in a heating mantle at an internal temperature of 97 ° C (+/- 5 ° C) and is maintained at that temperature until the reaction is complete (typical and about 40 hours) as determined by HPLC. After the reaction is complete, the heating is discontinued and the reaction is cooled to an internal temperature of about 20 ° C to 25 ° C with stirring, and the reaction is stirred for 2 to 3 hours.

Seed crystals (0.20 g, 0.85 mmoles) of 5- (4-methyl-piperazin-1-yl) -2-nitroaniline are added to the reaction mixture unless precipitation has already occurred. The water (2.450 ml) is added to the stirred reaction mixture over a period of about one hour while maintaining the internal temperature at a temperature in the range of about 20 ° C to 30 ° C. After the addition of water is complete, the resulting mixture is stirred for about one hour at a temperature of 20 ° C to 30 ° C. The resulting mixture is then filtered, and the flask and the filter paste are washed with water (3 x 2.56 1). The yellow gold solid product is dried at a constant weight of 416 g (98.6%) under vacuum at approximately 50 ° C in a vacuum oven. Procedure C 5-Chloro-2-nitroaniline (401 g, 2.32 moles) is added to a fixed 4-neck 12-liter round bottom flask with an overhead stirrer, condenser, gas inlet, addition funnel and thermometer probe . The flask is then purged with N2, 1-methylpiperazine (977 g, 1.08 1, 9.75 mol) and 100% ethanol (650 ml) are added to the reaction flask with stirring. The flask is again purged with N2, and the reaction is maintained under N2. The flask is heated in a heating mantle at an internal temperature of 97 ° C (+/- 5 ° C) and maintained at that temperature until the reaction is complete (typical and approximately 40 hours) as determined by HPLC. After the reaction is complete, the heating is discontinued and the reaction is cooled to an internal temperature of about 80 ° C with stirring, and water (3.15 1) is added to the mixture by means of an addition funnel over the mixture. the period of 1 hour while maintaining the internal temperature at 82 ° C (+/- 3 ° C). After the addition of water is completed, the heating is discontinued and the reaction mixture is allowed to cool over a period of not less than 4 hours at an internal temperature of 20-25 ° C. The reaction mixture is then stirred for an additional hour at an internal temperature of 20-30 ° C. The resulting mixture is then filtered, and the flask and filter cake are washed with water (1 x 1 L), 50% ethanol (1 x 1 L), and 95% ethanol (1 x). 1L). The yellow gold solid product is placed in a drying tray and dried at a constant weight of 546 g (99% yield) under vacuum at approximately 50 ° C in a vacuum oven.

B. Synthesis of [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -acetic acid ethyl ether Procedure A A 4-neck flask of 5000 ml is fixed with a stirrer, thermometer, condenser and gas inlet / outlet. The flask equipped with 265.7 g (1.12 moles, 1.0 equivalents) of 5- (4-methyl-piperazin-1-yl) -2-nitroaniline and 2125 ml of 200 proof EtOH is charged. The resulting solution is purged with N2 for 15 minutes. Then, 20.0 g of Pd at 5% / C (H20 at 50% w / w) are added. The reaction is vigorously stirred at 40-50 ° C (internal temperature) while H2 is bubbled through the mixture. The reaction is monitored every hour for the disappearance of 5- (4-methyl-piperazin-1-yl) -2-nitroaniline by HPLC. The typical reaction time is 6 hours. After all the 5- (4-methyl-piperazin-1-yl) -2-nitroaniline have disappeared from the reaction, the solution is purged with N2 for 15 minutes. Then, 440.0 g (2.25 moles) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride is added as a solid. The reaction is stirred at 40-50 ° C (internal temperature) until the reaction is complete. The reaction is monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time is 1-2 hours. After the reaction is complete, it is cooled to room temperature and filtered through a pad of Celite filtration material. The Celite filtration material is washed with absolute EtOH (2 x 250 ml) and the filtrate is concentrated under reduced pressure to give a thick brown / orange oil. The resulting oil is taken in 850 ml of a 0.37% HCl solution. The solid NaOH (25 g) is then added in one portion, and a precipitate is formed. The resulting mixture is stirred for 1 hour and then filtered. The solid is washed with H20 (2 x 400 ml) and dried at 50 ° C in a vacuum oven to provide 251.7 g (74.1%) of ethyl ester of [6- (4-methyl-piperazin-1-yl) ethyl ester) -lH-benzoimidazol-2-yl] acetic acid as a pale yellow powder. Procedure B A 4-neck, 5000 ml jacketed flask is fixed with a mechanical stirrer, condenser, temperature probe, gas inlet, and oil bubbler. The flask equipped with 300 g (1.27 mol) of 5- (4-methyl-piperazin-1-yl) -2-nitroaniline and 2400 ml of 200 EtOH test is charged (the reaction can be and has been carried out with ethanol at 95% and it is not necessary to use 200 test ethanol for this reaction). The resulting solution is stirred and purged with N2 for 15 minutes. Then, 22.7 g of 5% Pd / C (50% H / w) are added to the reaction flask. The reaction vessel is purged with N2- for 15 minutes. After purging with N2, the reaction vessel is purged with H2 by maintaining a slow but constant flow of H2 through the flask. The reaction is stirred at 45-55 ° C (internal temperature) while the H2 is bubbled through the mixture until 5- (4-methyl-piperazin-1-yl) -1-nitronaniline is completely consumed as described. determined by HPLC. The typical reaction time is 6 hours. After all of the 5- (4-methyl-piperazin-1-yl) -1-nitronaniline has disappeared from the reaction, the solution is purged with N2 for 15 minutes. The diamine intermediate is sensitive to air therefore be careful to avoid exposure to air. 500 g (2.56 moles) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride are added to the reaction mixture over a period of about 30 minutes. The reaction is stirred at 45-55 ° C (interval temperature) under N2 until the diamine is completely consumed as determined by HPLC. The typical reaction time is approximately 2 hours. After the reaction is complete, the reaction is filtered while hot through a pad of Celite. The reaction flask and Celite are then washed with 200 proof EtOH (3 x 285 ml). The filtrates are combined in a 5000 ml flask, and about 3300 ml of ethanol is removed under vacuum to produce an orange oil. Water (530 ml) and then IM HCl (350 ml) are added to the resulting oil, and the resulting mixture is stirred. The resulting solution is stirred vigorously while adding 30% NaOH (200 ml) over a period of about 20 minutes keeping the internal temperature at about 25-30 ° C while bringing the pH to between 9 and 10. The suspension is stirred resulting for approximately 4 hours while maintaining the internal temperature at approximately 20-25 ° C. The resulting mixture is filtered, and the filter cake is washed with H20 (3 x 300 ml). The collected solid is dried to a constant weight at 50 ° C under vacuum in a vacuum oven providing 345.9 g (90.1%) of ethyl ester of [6- (4-methyl-γ-piperazin-1-yl) -lH- acid. benzoimidazol-2-yl] acetic acid as a pale yellow powder. In an alternative development procedure, the filtrates are combined and the ethanol is removed under vacuum until at least about 90% has been removed. The water is then added in a neutral pH to the resulting oil, and the solution is cooled to about 0 ° C. Then 20% NaOH aqueous solution is added slowly with rapid stirring to bring the pH to 9.2 (read with the pH meter). The resulting mixture is then filtered and dried as described above. The alternative development procedure provides the light dark to light yellow product in yields as high as 97%. Methods to reduce the water content of [6- (4-methyl-piperazin-1-yl) -iH-benzoimidazol-2-yl] -acetic acid ethyl ester [6- (4-methyl-) ethyl ester] piperazin-1-yl) -lH-benzoimidazol-2-yl] -acetic acid (120.7 grams) which has been previously developed and dried to a water content of about 8-9% H20 is placed in a round bottom flask of 2000 ml and dissolved in absolute ethanol (500 ml). Concentrate the amber solution to a thick oil using a rotary evaporator with heating until all the solvent is removed. The procedure is repeated twice more. The thick oil thus obtained is left in the flask and placed in a vacuum oven heated at 50 ° C overnight. The results of the Karl Fisher analysis indicate a water content of 5.25%. The decreased water content obtained by this method provides increased yields in the procedure of the following Example. Other solvents such as toluene and THF can be used in place of ethanol by this drying process.

C. Synthesis of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one Procedure A The ethyl ester of [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -acetic acid (250 g, 820 mmol) is dissolved (dried with ethanol as described above) in THF (3800 ml) in a fixed 5000 ml flask with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) is added to the solution, and the internal temperature is increased to 40 ° C. When all the solids have dissolved and the temperature of the solution has reached 40 ° C, the solid KHMDS (376.2 g, 1890 mmol) is added over a period of 5 minutes. When the addition of the potassium base is completed, a heterogeneous yellow solution is obtained, and the internal temperature has been increased to 62 ° C. After a period of 60 minutes, the internal temperature decreases again to 40 ° C, and the reaction is determined to be complete by HPLC (no starting material or non-cyclized intermediate is present). The thick reaction mixture is then stopped by pouring into H20 (6000 ml) and stirring the reaction mixture until it has reached room temperature. The mixture is then filtered, and the filter pad is washed with water (1000 ml 2X). Place the bright yellow solid in a drying tray and dry in a vacuum oven at 50 ° C overnight providing 155.3 g (47.9%) of the 4-amino-5-fluoro-3- [6- (4 -methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one. Procedure B A 5000 ml 4-neck jacket flask is equipped with a distillation apparatus, a temperature probe, an N2 gas inlet, an addition funnel, and a mechanical stirrer. The ethyl ester of [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -acetic acid (173.0 g, 570 mmol) is charged to the reactor, and the reactor is purged with N2. for 15 minutes. The dry THF (2600 ml) is then charged into the flask with stirring. After all the solid has dissolved, the solvent is removed by distillation (vacuum or atmospheric) (the higher temperature helps remove the water) using heat as necessary. After 1000 ml of solvent has been removed,. the distillation is stopped and the reaction is purged with N2. 1000 ml of dry THF is then added to the reaction vessel, and when all the solid is dissolved, distillation is again carried out (vacuum or atmospheric) until another 1000 ml of solvent has been removed. This process of adding dry THF and solvent removal is repeated for at least 4 times (in the fourth distillation, 60% of the solvent is removed instead of only 40% as in the first 3 distillations) after which a sample is removed of 1 ml by Karl Fischer analysis to determine the water content. If the analysis shows that the sample contains less than 0.20% water, then the reaction is continued as described in the next paragraph. However, if the analysis shows more than 0.20% water, then the drying process described above is continued until a water content of less than 0.20% is achieved. After a water content of less than or about 0.20% is achieved using the procedure described in the previous paragraph, the distillation apparatus is replaced with a reflux condenser, and the reaction is loaded with 2-amino-6-fluoro -benzonitrile (66.2 g, 470 mmoles) (0.95 equivalents are used in some procedures). The reaction is then heated to an internal temperature of 38-42 ° C. When the internal temperature has reached 38-42 ° C, the solution of KHMDS (1313 g, 1.32 mmol, 20% of KHMDS in THF) is added to the reaction by means of the additional funnel over a period of 5 minutes maintaining the internal temperature at approximately 38-50 ° C during the addition. When the addition of the potassium base is completed, the reaction is stirred for 3.5 to 4.5 hours (in some examples it is stirred for 30 to 60 minutes and the reaction can be completed within that time) while maintaining the internal temperature of 38-42 ° C. A sample of the reaction is then removed and analyzed by HPLC. If the reaction is not completed, add the additional KHMDS solution to the flask over a period of 5 minutes and stir the reaction at 38-42 ° C for 45-60 minutes (the amount of KHMDS solution added is determined by the following : If the IPC ratio is <; 3.50, then 125 ml is added; yes 10.0 > CPI ratio > 3.50, then 56 ml are added; yes 20.0 > CPI ratio > 10, then 30 ml are added. The IPC ratio is equal to the area corresponding to 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2 ona) divided by the area corresponding to the non-cyclized intermediary). Once the reaction is completed (IPC ratio> 20), the reactor is cooled to an internal temperature of 25-30 ° C, and water (350 ml) is charged into the reactor over a period of 15 minutes while the internal temperature is maintained at. 25-35 ° C (in an alternative, the reaction is carried out at 40 ° C and the water is added within 5 minutes.The faster stop reduces the amount of impurities that forms over time). The reflux condenser is then replaced with a distillation apparatus and the solvent is removed by distillation (vacuum or atmospheric) using heat as required. After 1500 ml of solvent has been removed, the distillation is discontinued and the reaction is purged with N2. Water (1660 ml) is then added to the reaction flask while maintaining the internal temperature at 20-30 ° C. The reaction mixture is stirred at 20-30 ° C before cooling to an internal temperature of 5-10 ° C and then stirred for 1 hour. The resulting suspension is filtered, and the flask and filter cake are washed with water (3x 650 ml). The solid is dried in this way obtained at a constant weight under vacuum at 50 ° C in a vacuum oven to provide 103.9 g (42.6% yield) of 4-amino-5-fluoro-3- [6- (4- methyl-piperazin-1-yl) -1H-benzimidazol-2-yl] -lH-quinolin-2-one as a yellow powder. Procedure C toluene The ethyl ester of [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -acetic acid (608 g, 2.01 mol) is charged (dry) and 2-amino-6-fluoro -benzonitrile (274 g, 2.01 moles) in a 4-neck 4-neck flask fixed in a heating mantle and fixed with a condenser, mechanical stirrer, gas inlet, and temperature probe. The reaction vessel is purged with N2 and toluene (7.7 L) in the reaction mixture while stirring. The reaction vessel is again purged with N2 and kept under N2. The internal temperature of the mixture increases until a temperature of 63 ° C (+/- 3 ° C) is achieved. The internal temperature of the mixture is maintained at 63 ° C (+/- 3 ° C) while about 2.6 L of toluene is distilled from the flask under reduced pressure (380 +/- 10 torr, distillation head t = 40 ° C (+/- 10 ° C) (Karl Fischer analysis is used to check the water content in the mixture.) If the water content is greater than 0.03%, then add another 2.6 L of toluene and repeat the This process is repeated until the water content of less than 0.03% is reached.) After a water content of minus -0.03% is achieved, heating is discontinued, and the reaction is cooled under N2 to an internal temperature of 17-19 ° C. The potassium t-butoxide in THF (20% in THF, 3.39 kg, 6.04 mmoles of potassium t-butoxide) is then added to the reaction under N2 in a proportion of such form that the internal temperature of the reaction is kept below 20 ° C. After the addition of potassium t-butoxide is complete, the gite the reaction at an internal temperature of less than 20 ° C for 30 minutes. The temperature is then increased to 25 ° C, and the reaction is stirred for at least 1 hour. The temperature is then increased to 30 ° C, and the reaction is stirred for at least 30 minutes. The reaction is then monitored for completion using HPLC to check the consumption of the starting materials (typically in 2-3 hours, both starting materials are consumed (less than 0.5% in% HPLC area). complete after 2 hours, another 0.05 equivalents of potassium t-butoxide are added at a time, and the process is completed until the HPLC shows that the reaction is complete.After the reaction is completed, 650 ml of The reaction is then heated to an internal temperature of 50 ° C and the THF is distilled (approximately 3L by volume) under reduced pressure from the reaction mixture. L) in droplets to the reaction mixture using an addition funnel The mixture is then cooled to room temperature and stirred for at least 1 hour.The mixture is then filtered, and the filter paste is washed with water (1.2L ) with 70% ethanol (1.2 L), and with 95% ethanol (1.2 L). The bright yellow solid is placed in a drying tray and dried in a vacuum oven at 50 ° C until a constant weight is obtained which provides 674 g (85.4%) of the 4-amino-5-fluoro-3 - [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one. Purification of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one A 4-necked flask is placed, of 3000 ml with a condenser, temperature probe, N2 gas inlet, and mechanical stirrer in a heating mantle. The flask is then charged with 4-amino-4-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one (101.0 g , 0.26 moles), and the yellow solid is suspended in 95% ethanol (1000 ml) and stirred. In some cases an 8: 1 solvent ratio is used. The suspension is then heated to a gentle reflux (temperature of about 76 ° C) with stirring over a period of about 1 hour. The reaction is then stirred for 45-75 minutes while it is brought to reflux. At this point, the heating is removed from the flask and the suspension is allowed to cool to a temperature of 25-30 ° C. The suspension is then filtered, and the filter pad is washed with water (2 x 500 ml) A The yellow solid is then placed in a drying tray and dried in a vacuum oven at 50 ° C until a constant weight is obtained (typically 16 hours) to obtain 97.2 g (96.2%) of the product purified as a yellow powder.

D. Preparation of lactic acid salt of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -1H-bensimidazol-2-yl] -lH-quinolin-2-one D, L-Tactic Acid A 3000 ml 4-neck jacket flask is attached with a condenser, a temperature probe, a N2 gas inlet, and a mechanical stirrer. The reaction vessel is purged with N2 for at least 15 minutes and then charged with 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl. ] -lH-quinolin-2-one (484 g, 1. 23 moles). A solution of D, L-lactic acid is prepared (243. 3 g, 1. 72 moles of monomer see the next paragraph), water (339 ml), and ethanol (1211 ml) and then charged to the reaction flask. Agitation is initiated in a proportion of medium, and the reaction is heated to an internal temperature of 68-72 ° C. The internal temperature of the reaction is maintained at 68-72 ° C for 15-45 minutes and then the maintenance is discontinued. The resulting mixture is filtered through a grid of microwaves which collects the filtrate in a 12 L flask. The 12 liter flask is equipped with an internal temperature probe, a reflux condenser, an addition funnel, an inlet and gas outlet, and an upper agitator. The filtrate is then stirred in an average ratio and heated to reflux (internal temperature of about 78 ° C). While maintaining a gentle reflux, the ethanol (3, 596 ml) is charged to the flask over a period of about 20 minutes. The reaction flask is then cooled to an internal temperature in the range of about 64-70 ° C within 15-25 minutes and this temperature is maintained for a period of about 30 minutes. The glass reactor is inspected. If the crystals are not present, then the crystals of the lactic acid salt of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -1H-benzimidazol-2-yl] -lH-quinolin-2-one (484 mg, 0.1 mol%) is added to the flask, and the reaction is stirred at 64-70 ° C for 30 minutes before the glass flask is inspected again. Once the crystals are present, stirring is reduced to a low speed and the reaction is stirred at 64-70 ° C for an additional 90 minutes. The reaction is then cooled to about 0 ° C over a period of about 2 hours, and the resulting mixture is filtered through a filter screen of 25-50 microns.

The reactor is washed with ethanol (484 ml) and stirred until the internal temperature is about 0 ° C. The cold ethanol is used to wash the filter paste, and this procedure is repeated 2 more times. The collected solid is dried at a constant weight at 50 ° C under vacuum in a vacuum oven yielding 510.7 g (85.7%) of the crystalline yellow lactic acid salt of 4-amino-5-fluoro-3- [6- ( 4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one. A rubber press or inert conditions are typically used during the filtration process. While it appears that the dry solid is very hygroscopic, the wet filter paste tends to take up water and becomes sticky. Precautions are taken to avoid prolonged exposure of the wet filter paste to the atmosphere. Commercial lactic acid generally contains approximately 8-12% w / w of water, and contains dimers and trimers in addition to lactic acid monomer. The molar ratio of the lactic acid dimer to monomer is general and about 1.0: 4.7. The commercial grade lactic acid can be used in the process described in the preceding paragraph as the monolactate salt and preferentially precipitated from the reaction mixture. Identification of Metabolites Two metabolites of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -lH-quinolin-2-one have been identified. (Compound 1) and characterized in rat plasma collected from a 2-week toxicology study as described in references incorporated herein. The two metabolites identified are the compound N-oxide of piperazine (Compound 2) and the N-demethylated compound (Compound 3) are shown below.

Compound 2 Compound 3 IC5os of compounds 1-3 The kinase activity of a number of the protein tyrosine kinase is measured using the methods described in the various references incorporated herein. Some of these are shown in the following Table.

Table. IC50S of compounds 1-3 Synthesis of 4-amino-5-fluoro-3- [6- (4-methyl-4-oxidcpiperazin-1-yl) -lH-bensimidazol-2-yl] quinolin-2 (IH) -one (Ccropuesto 2) and 4-amino-5-fluoro-3- (6-piperazin-1-yl-1H-benzimidazol-2-yl) -quinolin-2 (1H) -one (Compound 3) To confirm the structures of the identified metabolites of the Compound 1, the metabolites are synthesized independently. Compound 2 synthesizes the N-oxide metabolite of compound 1 as shown in the subsequent scheme. Compound 1 is heated in a mixture of ethanol, dimethylacetamide and hydrogen peroxide. Upon completion of the reaction, compound 2 is isolated by filtration and washed with ethanol. If necessary, the product can be further purified by column chromatography.

Compound 3, the N-demethyl metabolite of Compound 1, is synthesized as shown in the subsequent scheme. The 5-chloro-2-nitroaniline is treated with piperazine to produce 4 which is subsequently protected with a (Bqc) butyloxycarbonyl group to produce 5. The reduction of the nitro group followed by condensation with 3-ethoxy-3-ethyl ester imipropionic gives 6. Condensation of 6 with 6-fluoroantranilonitrile using the potassium hexamethyldisilazide as the produced base 7. The crude product is treated with aqueous HCl to yield the desired metabolite as a yellow / brown solid after purification.

To identify the plasma biomarkers of the treatment with 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (1H), the metastatic mouse breast tumor model spontaneously 4T1, and circulating serum markers are analyzed by ELISA. : 4T1 breast tumor cells are grown as subcutaneous tumors in BALB / C mice, and treatment (10, 30, 60, 100 and 150 mg / kg) with 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -quinolin-2 ( ÍH) -one (Compound 1) starts when tumors have - approximately 150 mm3. The mice are dosed orally, daily for 18 days. The serum is collected from individual animals after 18 days, and the levels of circulating cell adhesion molecules, ICAM, VCAM and E-selectin slbules, are measured by ELISA assay. Figure 1 is a graph showing the effects of 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] quinolin-2 (1H) -one in the 4T1 murine breast tumor model. The growth of subcutaneous tumors is inhibited (40-80% compared to the control), liver metastasis is completely inhibited, and lung metastasis is inhibited by 60-97% after 18 days of dosing. The various data regarding the incidence of metastases are shown in Figure 1 and the following Table is included The wells of a "U" Maxisorb Nunc microtiter plate (# 449824) are coated with monoclonal capture antibody, rat anti-mouse VCAM-1 (R & D Systems # BCA12), in 5 μg / ml in buffered saline. with phosphate (PBS), 50 μl / well, and incubated at 37 ° C for 1 hour. The plates are washed 3 times with wash buffer [PBS containing 0.1% Tween 20 and 1% goat serum (Gibco BRL # 16210-072)]. The wells are blocked with 150 μl / well of wash buffer and incubated at 37 ° C for 1 hour. The blocking solution is removed from the wells and standards are diluted (VCAM-1 / Fc Cimera We derived from R & D Systems # 643-VM of recombinant mouse) and the samples in wash buffer and added to the wells The standard is used in a range of 4000 pg / ml to 31 pg- / ml. Serum samples 1/200 are diluted followed by serial dilutions 3 times. Samples and standards are added at 50 μ / well and incubated at 37 ° C for 1 hour. The plates are washed three times and incubated at 37 ° C for 1 hour with the primary antibody (VCAM-1 anti-mouse goat bioestate, R & amp; amp;; D Systems # BAF643) 1/2000 in wash buffer, 50 μL / well. The plates are washed as described above and incubated at 37 ° C for 1 hour with stepavidin-HRP (R &D Systems # DY998) 1/200 in PBS / 1% goat serum without Tween 20. The plates are washed three times with wash buffer and three times with PBS. They are then grown with TMB substrate (Kirkegaard &Perry labs # 50-76-00) 50 μL / well and incubated at room temperature for 10 minutes. The reaction is stopped with the addition of 50 μl / well H2SO4 4N, and the plates are read at 450-550 dual wavelength in the Vmax plate reader from Molecular Devices. The wells of a "U" bottom microtiter plate from Nunc Maxisorb (# 449824) are coated with monoclonal capture antibody, rat anti-mouse ICAM-1 (R &D Systems # BSA2), at 5 μg / ml in phosphate buffered saline (PBS), 50 μl / well and incubated at 37 ° C for 1 hour. The plates are washed 3 times with wash buffer [PBS confiding Tween 20 at 0.1% and Carnation Nonfat Dry milk at 1%]. The wells are blocked with 150 μl / well of wash buffer-and incubated at 37 ° C for 1 hour. The blocking solution is removed from the wells and the standard (a pool of serum from mice implanted with KMl2L4a or 4T1-tumors) and diluted-the samples in water buffer and added to the wells. The standard is used in a dilution range of 1 / 10-1 / 1280. Serum samples are diluted 1/15 followed by serial dilutions 3 times. Samples and standards are added in 50 μl / wells and incubated at 37 ° C for 1 hour. The plates are washed three times and incubated at 37 ° C for 1 hour with the primary antibody (goat anti-ICAM-1, Santa Cruz Biotechnology # sc-1511) diluted 1/250 in wash buffer, 50 μL / well . The plates are washed as above and incubated at 37 ° C for 1 hour with 50 μL / well of the secondary antibody (IgG labeled anti-pigment HRPO, Caltag # G50007) 1/2000 in wash buffer. The plates are washed three times with wash buffer and three times with PBS, then grown with TMB substrate (Kirkegaard &Perry Labs # 50-76-00) 50 μL / well and incubated at room temperature for 10 minutes. The reaction is stopped with the addition of 50 μl / well of 4N H2SO4, and the 3n 450-550 dual wavelength plates are read on the Vmax plate reader from Molecular Devices. The serum samples are tested by the #MESCO mouse E-selectin immunoassay kit from R &D Systems Quantikine M, according to the manufacturer's protocol. Human colon Xenografts KM12L4a in vivo Female Nu / nu mice (6-8 weeks of age, 18-22 grams) are obtained from Charles River Laboratories (Wilmington, MA). The tumor cells (2 x 106 KMl2L4a) are implanted subcutaneously in the flask of mice and allowed to grow to the desired size before the treatment is started. It is administered to mice that have tumor with 100 mg / kg of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazol-2-yl] -quinolin-2 (H) -one for 7 days and the individual mice are euthanized. The tumors are resected and frozen rapidly in liquid nitrogen. Zimography for activity of MMP-2 and MMP-9 Resected tumors are lysed in buffer RIPA (Nonidet P-40 1%, sodium deoxylate 0.5%, sodium dodecyl sulfate in phosphate buffered saline IX, pH 7.2) containing protease inhibitors (Roche Molecular Biochemicals) and phosphatase inhibitors (Sigma). 50 μg of the total proteins are analyzed by zymography of gelatin in 12% SDS polyacrylamide with gelatin substrate. After electrophoresis, the gels are washed twice for 15 minutes in 2.5% Triton X-100, incubated overnight at 37 ° C in 50 mM Tris-HCl and 10 mM CaCl2, pH 7.6 and stained with blue of Comassie to 0.5% and destain with 50% methanol. ELISA VEGF-A protein levels are quantified in KM12L4a tumor lysates using a commercially available ELISA kit (R and D Systems, Minneapolis, MN) according to the manufacturer's procedures. The analysis of human colon tumors KM12L4a, removed after in vivo administration of 4-amino-5- fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin- 2 (ÍH) -one, shows reduced VEGF production and decreased activity of MMP-9. These changes are accompanied by decreased tumor cell proliferation (Ki67), induced apoptosis (increased PARP cleavage and caspase-3) and reduced vascular density (CD31) as observed by immunohistochemical antibody staining. The preparation of numerous useful benzimidazole quinoline compounds to inhibit angiogenesis • and tyrosine kinases of the vascular endothelial growth factor receptor and to inhibit other tyrosine and serine / threonine kinases including 4-amino-5-fluoro-3- [5- (4-methylpiperazin-1-yl) -lH- benzimidazol-2-yl] quinolin-2 (lH) -one or a tautomer thereof is described in the following documents which are each incorporated herein by reference in their entirety and for all purposes as fully indicated in the present: Patent of the United States of America No. 6, 605,617, Patent of the United States of America No. 6,756,383; US Patent Application No. 10 / 116,117 filed (published February 6, 2003, as the Application of the United States of America 2003/0028018 Al); Application of the United States of America No. 10 / 644,055 (published May 13, 2004, United States of America Patent Application No.2004 / 0092535); Application of the United States of America No. 10 / 983,174; Application of the United States of America No. 10 / 706,328, (published on November 4, 2004, as 2004/0220196); Patent Application of the United States of America No. 10 / 982,757; and Application of United States of America No. 10 / 982,543. Western Blot Analysis HUVEC are cultured in EGM (Endothelial Cell Growth Medium) with or without 100 mM of 4-amino-5-fluoro-3- [6- (4-methyl-piperazin-1-yl) -lH-benzimidazole-2. -yl] quinolin-2 (lH) -one (Compound 1), and cell lysates are harvested at 0, 16, and 24 hours post-treatment. Equal amounts of protein are loaded in 4-20% SDS-PAGE, and the gels are probed with antibodies against ICAM, VCAM, a5 integrin, and av integrin. Equal loading and efficiency are evaluated by probing with anti-β-actin antibody. The expression of ICAM, VCAM and a5 integrin is decreased with treatment with 4-amino-5-fluoro-3- [6- (4-methylpiperazin-1-yl) -lH-benzimidazol-2-yl] quinolin-2 (1H -one in HUVEC in vitro. It should be understood that the organic compounds according to the invention can exhibit the phenomenon of tautomerism. Since the chemical structures within this specification can only represent one of the possible tautomeric forms at a time, it should be understood that the invention comprises any tautomeric form of the drawn structure. For example, the compound of Structure IIIB is shown below with a tautomer, Tautomer IIIBa: Tautomer IIIBa Other tautomers of the compound of Structure IIIB, tautomer IIIBb and Tautomer IIIBc, are shown below ^: tautomer IIIBb Tautomer IIIBc All documents or references cited herein are incorporated herein by reference in their entirety and for all purposes as if fully indicated herein. It should be understood that the invention is not limited to the embodiments set forth herein for illustration, but comprises all such forms thereof as are within the scope of the invention. It is noted that in relation to this date, the best method known by the applicant to carry out the said invention, is that which is clear from the present "description of the invention."

Claims (39)

1. CLAIMS Having described the invention as above, the content with the following claims is claimed as property: 1. A method for modulating an inflammatory response and / or reducing cell adhesion in a subject, characterized in that it comprises: administering to the subject a compound of the Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the inflammatory response is modulated in the subject and / or cell adhesion is reduced in the subject after of the administration, and Structure I has the following formula: Wherein, R1, R2, R3 and R4 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -N02, -OH, -OR15, groups - NR16R17, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, groups substituted and unsubstituted heterocyclyl, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, (alkyl) (aryl) aminoalkyl groups substituted and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups and -C (= 0) groups R18. R5, R6, R7 and R8 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, groups -N02, -OH, -OR19, -NR20R21 groups, -SH groups, -SR22, -S (= 0) R23 groups, -S (= 0) 2R24 groups, substituted and unsubstituted CN, amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, groups substituted and unsubstituted diarylaminoalkyl groups (alkyl) (aryl) substituted and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) R25 groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, groups substituted and unsubstituted alkoxyalkyl, aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups; R 12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH groups, alkoxy, aryloxy groups, -NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, alkylamino groups substituted and unsubstituted, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amiino groups, -C (= 0) H, -C (= 0) -alkyl groups, -C (= 0) -aryl groups, -C (= 0) O groups -alkyl, groups -C (= 0) O-aryl, C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl, groups -C (= 0 ) N (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) (alkyl) (aryl), groups -C (= 0) -heterocyclyl, groups -C (= 0 ) NH (heterocyclyl), groups -C (= 0) -N (heterocyclyl) 2, groups -C (= 0) -N (alkyl) (heterocyclyl), groups -C (= 0) -N (aryl) (heterocyclyl) ), substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups R15 and R19 may be the same or different and are independently selected of the group consisting of substituted and unsubstituted alkyl groups, substituted and non-substituted aryl groups tuidos, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) H, -C (= 0) -alkyl, C (= 0) -aryl, -C (= 0) groups NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl), groups C (= 0) N (alkyl) 2, groups -C (= 0) (aryl) 2, groups -C (= 0) (alkyl) (aryl), substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, groups (alkyl) (aryl) substituted and unsubstituted, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted (heterocyclyl) (aryl) aminoalkyl groups and not substituted, substituted alkoxyalkyl groups and unsubstituted, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R16 and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -C (= 0) H groups, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl) , groups C (= 0) N (alkyl) 2, groups C (= 0) (aryl) 2, groups C (= 0) N (alkyl) (aryl), groups C (= 0) 0-alkyl, C (= 0) 0-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted diarylaminoalkyl groups and not substituted, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, -C (= 0) -heterocyclyl groups, -C (= 0) -0-heterocyclyl groups, group s -C (= 0) NH (heterocycle), groups -C (= 0) -N (heterocyclyl) 2, groups -C (= 0) - N (alkyl) (heterocyclyl), groups -C (= 0) - N (aryl) (heterocyclyl), substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R18, R23, R24, and R25 can be the same or different or are independently selected from the group consisting of H, -NH2, -NH (alkyl) groups, -NH (aryl) groups, - (alkyl) groups, 2 groups -N (aryl) 2, -N (alkyl) (aryl) groups, NH groups (heterocyclyl), -N (heterocyclyl) groups (alkyl), -N (heterocyclyl) groups (aryl), -N (heterocyclyl) groups , substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, -OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, -NHOH groups, -N (alkyl) OH groups ), -N (aryl) OH groups, - (alkyl) -O-alkyl groups, -N (aryl) O-alkyl groups, N- (alkyl) O-aryl groups, and - (aryl) O-aryl groups; and R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
2. 2. The method according to claim 1, characterized in that the levels of circulating adhesion molecules are reduced in the subject after administration. The method according to claim 1, characterized in that the amount of at least one inducible cell adhesion molecule, vascular cell adhesion molecules, or endothelial leukocyte adhesion molecule is reduced in the subject after administration. 4. The method according to claim 1, characterized in that it further comprises measuring the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule or endothelial leukocyte adhesion molecule in the subject after administration of the compound, the tautomer, the salt of the pharmaceutically acceptable compound, the pharmaceutically acceptable salt of the tautomer, or the rock thereof. 5. The method according to claim 1, characterized in that the amount of a matrix metalloprotease is reduced in the subject after administration. The method according to claim 5, characterized in that the matrix metalloprotease is matrix metalloprotease 2 or matrix metalloprotease 9. 7. The method according to claim 1, characterized in that the compound of Structure I is a compound of Structure II, and Structure II has the following formula: p Where A is a group which has one of the following Structures: Where Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms. The method according to claim 7, characterized in that Ra is a methyl group, and the compound of Structure II has Structure IIA having the following formula: 9. The method according to claim 8, characterized in that the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. The method according to claim 7, characterized in that Ra is a hydrogen, and the compound of Structure II has Structure IIB that the following formula: ? B 11. The method according to claim 7, characterized in that Ra is a methyl group, and the compound of Structure II has the Structure IIC having the following formula pc 12. The method according to claim 1, characterized in that the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. 13. The method according to claim 1, characterized in that the subject is a patient with cancer. 14. The method according to claim 1, characterized in that R12 and R13 are both H. The method according to claim 1, characterized in that at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group. The method according to claim 1, characterized in that at least one of R6 or R7 is a substituted or unsubstituted piperazine group. 17. The method according to claim 1, characterized in that R1 is F and R2, R3, R4, R5 and R8 are each H and one of R6 or R7 is H. 18. A method for identifying a subject in need of a compound of Structure 1, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, characterized in that it comprises measuring the amount of at least one cell adhesion molecule in the subject, before, during or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject, wherein the molecule of cell adhesion is selected from the inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule, and Structure I has the following f Ormula: Wherein, R1, R2, R3 and R4 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -N02, -OH, -OR15, groups - NR16R17, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, groups substituted and unsubstituted heterocyclyl, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, groups (alkyl) (aryl) substituted and unsubstituted aminoalkyl, substituted and unsubstituted heterocyclylalkyl groups and groups -C (= 0) R18. R5, R6, R7 and R8 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, groups -N02, -OH, -OR19, -NR20R21 groups, -SH groups, -SR22, -S (= 0) R23 groups, -S (= 0) 2R24 groups, -CN groups, substituted amidinyl groups and substituted, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, groups substituted and unsubstituted alkylaminoalkyl, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, groups -C (= 0) R25, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, hydroxyalkyl groups substituted and unsubstituted ilo, substituted and unsubstituted alkoxyalkyl groups, aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups; R 12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R13 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH groups, alkoxy, aryloxy groups, -NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, alkylamino groups substituted and unsubstituted, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amiino groups, -C (= 0) H, -C groups (= 0) -alkyl, groups -C (= 0) -aryl, groups -C (= 0) O-alkyl, groups -C (= 0) O-aryl, C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl, groups -C (= 0) N (alkyl ) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), groups -C (= 0) -heterocyclyl, groups -C (= 0) NH ( heterocyclyl), -C (= 0) -N (heterocyclyl) 2 groups, -C (= 0) -N (alkyl) (heterocyclyl) groups, -C (= 0) - (aryl) (heterocyclyl) groups, heterocyclylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups. R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C ( = 0) H, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), - groups -C ( = 0) H (aryl), groups C (= 0) (alkyl) 2, groups -C (= 0) N (aryl) 2, groups C (= 0) N (alkyl) (aryl) ,. substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, heterocyclylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted hydroxyalkyl groups and not substituted, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R16 and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -C (= 0) H groups, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl) , groups -C (= 0) (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), groups -C (= 0) 0- alkyl, C (= 0) 0-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, diarylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, -C (= 0) -heterocyclyl groups, -C (= 0) -0-heterocyclyl groups, g Rings -C (= 0) H (heterocycle), groups -C (= 0) -N (heterocyclyl) 2, groups -C (= 0) -N (alkyl) (heterocyclyl), groups -C (= 0) - N (aryl) (heterocyclyl), substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R18, R23, R24, and R25 may be the same or different or are independently selected from the group consisting of H, -NH2, -NH (alkyl) groups, -NH (aryl) groups, -N (alkyl) 2 groups, groups -N (aryl) 2, - (alkyl) (aryl) groups, NH (heterocyclyl) groups, -N (heterocyclyl) (alkyl) groups, - (heterocyclic) (aryl) groups, -N (heterocyclyl) 2 groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, -OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, -NHOH groups, -N (alkyl) OH groups) , -N (aryl) OH groups, -N (alkyl) -O-alkyl groups, - (aryl) O-alkyl groups, N- (alkyl) O-aryl groups, and -N (aryl) O-aryl groups; and R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. The method according to claim 18, characterized in that the compound of Structure I is a compound of Structure II, and Structure II has the following formula: p Where A is a group which has one of the following Structures: -1-N v_y N Ra or -? F-N x N Ra Where Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms. 20. The method of compliance with the claim 19, characterized in that Ra is a methyl group, and the compound of Structure II has Structure IIA having the following formula: IIA 21. The method according to claim 20, characterized in that the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. 22. The method according to claim 19, characterized in that Ra is a hydrogen, and the compound of Structure II has Structure 1IB having the following formula: HB 23. The method according to claim 19, characterized in that Ra is a methyl group, and the compound of Structure II has the Structure IIC having the following formula pc 24. The method according to claim 18, characterized in that the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. 25. The method according to claim 18, characterized in that the patient is a patient with cancer. 26. The method according to claim 18, characterized in that R12 and R13 are both H. 27. The method according to claim 18, characterized in that at least one of R6 or R7 is a substituted or unsubstituted heterocyclyl group. 28. The method according to claim 18, characterized in that at least one of R6 or R7 is a substituted or unsubstituted piperazine group. 29. The method according to claim 18, characterized in that R1 is F and R2, R3, R4, R5 and R8 are each H and one of R6 or R7 is H. 30. The method according to claim 18, further characterized in that it comprises extracting a blood sample from the subject and measuring the amount of at least one cell adhesion molecule in at least a portion of the sample. 31. A method for monitoring the progression of a disease or treatment in a subject, characterized in that it comprises measuring the amount of at least one molecule of cell adhesion in the subject after administration of the compound of Structure I, the tautomer of the compound , the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject, wherein the cell adhesion molecule is selected from cell adhesion molecule inducible molecule vascular cell adhesion molecule or adhesion of endothelial leukocyte, and Structure I has the following formula: Wherein, R1, R2, R3 and R4 may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -CN, -N02, -OH, -OR15, groups - NR16R17, amidinyl groups, substituted and unsubstituted, substituted guanidinyl groups and unsubstituted, groups primary, secondary and tertiary substituted alkyl and unsubstituted, substituted aryl groups and unsubstituted, substituted alkenyl groups and unsubstituted, substituted alkynyl groups and unsubstituted, groups substituted heterocyclyl and unsubstituted, substituted aminoalkyl groups and unsubstituted, substituted alkylaminoalkyl groups and unsubstituted, substituted dialkylaminoalkyl groups and unsubstituted arylaminoalkyl groups substituted and unsubstituted, substituted diarylaminoalkyl groups and unsubstituted, (alkyl) (aryl) aminoalkyl substituted and unsubstituted, substituted and unsubstituted heterocyclylalkyl groups and -C (= 0) R groups 18 R5, R6, R7 and R8 can be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, groups -N02, -OH, -OR19, -NR20R21 groups, -SH groups, - SR22, -S (= 0) R23 groups, -S (= 0) 2R24 groups, substituted and unsubstituted CN, amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary and tertiary alkyl groups, groups substituted and unsubstituted aryl, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, diarylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted (alkyl) (aryl) arylaminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C (= 0) R25 groups, ami groups substituted and unsubstituted nonalkyl, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups; R 12 is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R13 is selected from the group consisting of H, groups. substituted and unsubstituted alkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -OH groups, alkoxy, aryloxy groups, -NH2, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, alkylaminoalkyl groups substituted and unsubstituted, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkylamino groups, arylamino substituted groups and unsubstituted, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl) (aryl) amiino groups, -C (= 0) H, -C (= 0) -alkyl groups, -C (= 0) -aryl, groups -C (= 0) O-alkyl, groups -C (= 0) 0 -aryl, C (= 0) NH2, groups -C (= 0) NH (alkyl) lo), groups -C (= 0) NH (aryl, groups -C (= 0) N (alkyl) 2, groups -C (= 0) N (aryl) 2, groups-C (= 0) N (alkyl) ) (aryl), -C (= 0) -heterocyclyl groups, - C (= 0) NH (heterocyclyl) groups, -C (= 0) - (heterocyclyl) 2 groups, -C (= 0) -N groups alkyl) (heterocyclyl), -C (= 0) -N (aryl) (heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups and substituted and unsubstituted heterocyclyloxyalkyl groups. R15 and R19 may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, -C ( = 0) H, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) ) NH (aryl), groups -C (= 0) N (alkyl) 2, groups -C (= 0) (aryl) 2, groups -C (= 0) N (alkyl) (aryl), substituted aminoalkyl groups and unsubstituted, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups , substituted diheterocyclylaminoalkyl groups and not substituted, substituted and unsubstituted (heterocyclyl) (alkyl) aminoalkyl groups, substituted and unsubstituted (heterocyclyl) (aryl) aminoalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, groups substituted and unsubstituted heterocyclyloxyalguyl; Rld and R20 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. R17 and R21 may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, -C (= 0) H groups, -C (= 0) -alkyl, groups -C (= 0) -aryl, -C (= 0) NH2, groups -C (= 0) NH (alkyl), groups -C (= 0) NH (aryl) , groups C (= 0) N (alkyl) 2, groups -C (= 0) N (aryl) 2, groups -C (= 0) N (alkyl) (aryl), groups -C (= 0) O- I rent, -C (= 0) 0-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted diarylaminoalkyl groups and unsubstituted, substituted and unsubstituted (alkyl) (aryl) aminoalkyl groups, -C (= 0) -heterocyclyl groups, -C (= 0) -O-heterocyclyl groups, -C (= 0) NH groups (heterocycle) ), groups -C (= 0) - (heterocyclyl) 2, groups -C (= 0) - N (alkyl) (heterocyclyl), groups -C (= 0) -N (aryl) (heterocyclyl), substituted heterocyclylaminoalkyl groups and unsubstituted, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclyloxyalkyl groups; R18, R23, R24, and R25 can be the same or different or are independently selected from the group consisting of H, -NH2, -NH (alkyl) groups, -NH (aryl) groups, - (alkyl) groups, 2 groups -N (aryl) 2, - (alkyl) (aryl) groups, NH groups (heterocyclyl), -N (heterocyclyl) groups (alkyl), -N (heterocyclyl) groups (aryl), -N (heterocyclyl) 2 groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, -OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, -NHOH groups, -N (alkyl) OH groups ), -N (aryl) OH groups, -N (alkyl) -O-alkyl groups, -N (aryl) O-alkyl groups, N- (alkyl) O-aryl groups, and - (aryl) O-aryl groups; and R22 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. 32. The method according to claim 31, characterized in that the compound of Structure I is a compound of Structure II, and Structure II has the following formula: p Where A is a group which has one of the following Structures: Where Ra is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms. 33. The method according to claim 32, characterized in that Ra is a methyl group, and the compound of Structure II has Structure IIA having the following formula: ?TO 34. The method in accordance with the claim 33, characterized in that the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt. 35. The method according to claim 32, characterized in that Ra is a hydrogen, and the compound of Structure II has Structure IIB having the following formula: ? B 36. The method in accordance with the claim 32, characterized in that Ra is a methyl group, and the compound of Structure II has the Structure IIC having the following formula pc 37. The method in accordance with the claim 31, characterized in that the patient is a patient with cancer. 38. The method according to claim 31, characterized in that R12 and R13 are both H. 39. The method according to claim 31, characterized in that it comprises extracting a blood sample from the subject and then measuring the amount of at least one cell adhesion molecule in at least a portion of the sample.